Novel aspirin derivatives and uses thereof

ABSTRACT

The present invention provides novel aspirin derivatives useful for preventing and/or treating cancer. The novel compounds of this invention may be particularly useful for the prevention and/or treatment of cancers affecting the gastrointestinal system, such as colorectal cancer.

RELATED APPLICATIONS

This application is a continuation of and claims priority to U.S.application Ser. No. 13/918,394, filed Jun. 14, 2013, now U.S. Pat. No.9,187,402, which claims benefit of U.S. Provisional Patent ApplicationSer. Nos. 61/791,826, filed Mar. 15, 2013, and 61/659,647, filed Jun.14, 2012, the disclosure of each of which is incorporated herein byreference in its entirety.

STATEMENT OF FEDERAL SUPPORT

This invention was made with government support under1-R03-CA159353-01A1, awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

FIELD OF THE INVENTION

The present invention generally relates to novel aspirin derivatives andthe prevention and/or treatment of disorders responsive to aspirinderivatives.

BACKGROUND

Colorectal cancer (CRC) is a significant global health concern and isthe third leading cause of death from cancer among both men and womenworldwide.

Observational studies and randomized trials have demonstrated an inverseassociation between the incidence of CRC and the use of aspirin(acetylsalicylic acid), and aspirin has been shown to inhibit CRCtumorigenesis in various animal studies.

Because chronic aspirin administration gives rise to a number of adverseeffects, including, but not limited to, gastrointestinal (GI)disturbances such as dyspepsia, gastroduodenal bleeding, gastriculceration and gastritis, its usefulness in the prevention and/ortreatment of CRC is limited.

There is thus a need for improved aspirin therapies to prevent and treatCRC.

SUMMARY OF THE INVENTION

The present invention provides aspirin derivatives and methods of makingand using the same.

A first aspect of the present invention is a composition comprising,consisting essentially of or consisting of a compound of Formula I, II,III, IV, V, VI or VII.

A second aspect of the present invention is a pharmaceutical compositioncomprising, consisting essentially of or consisting of a compound ofFormula I, II, III, IV, V, VI or VII and a pharmaceutically acceptablecarrier.

A third aspect of the present invention is a method of producing acompound of Formula I, II, III, IV, V, VI or VII. In some embodiments,the method comprises, consists essentially of or consists of conjugatinga first moiety and a second moiety, wherein the first moiety is aspirin,an aspirin analog or an aspirin derivative and the second moiety isstilbene (1,2-diphenylethene), an analog or derivative of stilbene,gingerol (6-gingerol;5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone), an analogderivative of ginergol, shogaol (6-shogaol;1-(4-Hydroxy-3-methoxyphenyl)dec-4-en-3-one), an analog or derivative ofshogaol, zingerone (4-(4-hydroxy-3-methoxyphenyl)-2-butanone) or ananalog or derivative of zingerone.

A fourth aspect of the present invention is a method of preventingand/or treating a disorder in a subject in need thereof, comprising,consisting essentially of or consisting of administering to said subjecta therapeutically effective amount of a composition comprising,consisting essentially of or consisting of a compound of Formula I, II,III, IV, V, VI pr VII.

A fifth aspect of the present invention is a method of preventing and/ortreating a disorder in a subject in need thereof, comprising, consistingessentially of or consisting of administering to said subject apharmaceutical composition comprising, consisting essentially of orconsisting of a compound of Formula I, II, III, IV, V, VI or VII and apharmaceutically acceptable carrier.

A sixth aspect of the present invention is a kit for preventing and/ortreating a disorder in a subject comprising, consisting essentially ofor consisting of a compound or pharmaceutical composition of the presentinvention and instructions for using the compound or pharmaceuticalcomposition.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIG. 1, Panel A shows the effects of aspirin (As), resveratrol (Res),4′-aspirinated resveratrol (RAS), 1-aspirinated resveratrol (RAS-1), andthe combination of resveratrol and aspirin (Res+As) on the growth ofHCT-116 and HT-29 human colon cancer cells. FIG. 1, Panel B shows theeffects of aspirin (As), methylated-resveratrol (MRes),methylated-resveratrol aspirinate (MRAS) and the combination of MRes andaspirin (MRes+As) on the growth of HCT-116 and HT-29 human colon cancercells. FIG. 1, Panel C shows the effects of aspirin (As), pterostilbene(Pt), pterostilbene-aspirinate (PAS), and the combination ofpterostilbene and aspirin (Pt+As) on the growth of HCT-116 and HT-29human colon cancer cells.

FIG. 2 shows the effects of 6-shogaol (6-s), 6-shogaol aspirinate (SAS),combination of 6-shogaol and aspirin (6-s+As), and aspirin (As) on thegrowth of HCT-116 and HT-29 human colon cancer cells and H1299 humanlung cancer cells.

FIG. 3 shows the effects of 6-gingerol (6g), aspirin (As), 6-gingerolaspirinate (GAS), and combination of 6-gingerol and aspirin (6g+As) onthe growth of HCT-116 and HT-29 human colon cancer cells and H11299human lung cancer cells.

FIG. 4 shows the effects of aspirin and resveratrol (A/R), RAS, RAS-1,152 and 131 on the growth of HCT-116 and HT-29 human colon cancer cellsat various concentrations.

FIG. 5 shows liquid chromatography (LC) chromatograms of urine samplescollected from PAS-treated mice obtained using positive APCI-MSinterface: (A) before and (B) after enzymatic hydrolysis (treated withβ-glucuronidase and sulfatase); using negative ESI-MS interface: (C)before and (D) after enzymatic hydrolysis.

DETAILED DESCRIPTION

The foregoing and other aspects of the present invention will now bedescribed in more detail with respect to compositions and methodologiesprovided herein.

This description is not intended to be a detailed catalogue of all theways in which the present invention may be implemented or of all thefeatures that may be added to the present invention. For example,features illustrated with respect to one embodiment may be incorporatedinto other embodiments, and features illustrated with respect to aparticular embodiment may be deleted from that embodiment. Thus, one ormore of the method steps included in a particular method describedherein may, in other embodiments, be omitted and/or performedindependently. In addition, numerous variations and additions to theembodiments suggested herein, which do not depart from the instantinvention, will be apparent to those skilled in the art in light of theinstant disclosure. Hence, the following description is intended toillustrate some particular embodiments of the invention, and not toexhaustively specify all permutations, combinations and variationsthereof. It should therefore be appreciated that the present inventionis not limited to the particular embodiments set forth herein. Rather,these particular embodiments are provided so that this disclosure willconvey the full scope of the invention to those skilled in the art.

The terminology used herein is for the purpose of describing particularembodiments of the present invention only and is not intended to limitthe present invention.

Although the following terms are believed to be well understood by oneof skill in the art, the following definitions are set forth tofacilitate understanding of the presently disclosed subject matter.

All technical and scientific terms used herein, unless otherwise definedbelow, are intended to have the same meaning as commonly understood byone of ordinary skill in the art. References to techniques employedherein are intended to refer to the techniques as commonly understood inthe art, including variations on those techniques or substitutions ofequivalent techniques that would be apparent to one of skill in the art.

As used herein, the terms “a” or “an” or “the” may refer to one or morethan one. For example, “a” pharmaceutically acceptable excipient canmean one pharmaceutically acceptable excipient or a plurality ofpharmaceutically acceptable excipients.

As used herein, the term “about,” when used in reference to a measurablevalue such as an amount of mass, dose, time, temperature, and the like,is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1%of the specified amount.

As used herein, the term “and/or” refers to and encompasses any and allpossible combinations of one or more of the associated listed items, aswell as the lack of combinations when interpreted in the alternative(“or”).

As used herein, the term “cancer” refers to any benign or malignantabnormal growth of cells. Examples include, without limitation, breastcancer, prostate cancer, lymphoma, skin cancer, pancreatic cancer, coloncancer, colorectal cancer, melanoma, malignant melanoma, ovarian cancer,brain cancer, primary brain carcinoma, head-neck cancer, glioma,glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer,head or neck carcinoma, breast carcinoma, ovarian carcinoma, lungcarcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma,testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomachcarcinoma, colon carcinoma, prostatic carcinoma, genitourinarycarcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiplemyeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma,adrenal cortex carcinoma, malignant pancreatic insulinoma, malignantcarcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignanthypercalcemia, cervical hyperplasia, leukemia, acute lymphocyticleukemia, chronic lymphocytic leukemia, acute myelogenous leukemia,chronic myelogenous leukemia, chronic granulocytic leukemia, acutegranulocytic leukemia, hairy cell leukemia, neuroblastoma,rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essentialthrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissuesarcoma, osteogenic sarcoma, primary macroglobulinemia, andretinoblastoma. In some embodiments, the cancer is selected from thegroup of tumor-forming cancers. In some embodiments, the cancer iscolorectal cancer or lung cancer.

As used herein, the term “consists essentially of” (and grammaticalvariants thereof), as applied to the compositions and methods of thepresent invention, means that the compositions/methods may containadditional components so long as the additional components do notmaterially alter the composition/method. The term “materially alter,” asapplied to a composition/method of the present invention, refers to anincrease or decrease in the effectiveness of the composition/method ofat least about 20% or more. For example, a component added to acomposition of the present invention would “materially alter” thecomposition if it increases or decreases the composition's ability toinhibit tumor growth by at least 20%.

As used herein, the term “derivative” refers to a compound that isstructurally related to and can be derived from a second compound. Thus,an aspirin derivative is a compound that is structurally related to andcan be derived from aspirin.

As used herein, the term “emulsion” refers to a suspension or dispersionof one liquid within a second immiscible liquid. In some embodiments,the emulsion is an oil-in-water emulsion or a water-in-oil emulsion. Insome embodiments, “emulsion” may refer to a material that is a solid orsemi-solid at room temperature and is a liquid at body temperature(about 37° C.).

As used herein, the terms “increase” and “enhance” (and grammaticalvariants thereof) refer to an increase in the specified parameter of atleast about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%,175%, 200%, 250%, 300% or more.

As used herein, the terms “inhibit” and “reduce” (and grammaticalvariants thereof) refer to a decrease in the specified parameter of atleast about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more.

As used herein, the term “optionally substituted” refers to a chemicalstructure that may comprise one or more substituents. Optionallysubstituted structures may comprise any suitable substituent, including,but not limited to, F, Cl, Br, I, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH,O—C₁₋₆alkyl, C₁₋₆alkyl, and C₁₋₆ alkoxy.

As used herein, “pharmaceutically acceptable” means that the material issuitable for administration to a subject and will allow desiredtreatment to be carried out without giving rise to unduly deleteriousadverse effects. The severity of the disease and the necessity of thetreatment are generally taken into account when determining whether anyparticular side effect is unduly deleterious.

As used herein, the terms “prevent,” “preventing,” and “prevention” (andgrammatical variants thereof) refer to avoidance, prevention and/ordelay of the onset of a disease, disorder and/or a clinical symptom(s)in a subject and/or a reduction in the severity of the onset of thedisease, disorder and/or clinical symptom(s) relative to what wouldoccur in the absence of the compositions and/or methods of the presentinvention. In some embodiments, prevention is complete, resulting in thetotal absence of the disease, disorder and/or clinical symptom(s). Insome embodiments, prevention is partial, resulting in reduced severityand/or delayed onset of the disease, disorder and/or clinicalsymptom(s).

As used herein, the term “prevention effective amount” (and grammaticalvariants thereof) refers an amount that is sufficient to prevent and/ordelay the onset of a disease, disorder and/or clinical symptoms in asubject and/or to reduce and/or delay the severity of the onset of adisease, disorder and/or clinical symptoms in a subject relative to whatwould occur in the absence of the methods of the invention. Thoseskilled in the art will appreciate that the level of prevention need notbe complete, as long as some benefit is provided to the subject.

As used herein, the term “subject” (and grammatical variants thereof)refers to mammals, avians, reptiles, amphibians, or fish. Mammaliansubjects may include, but are not limited to, humans, non-human primates(e.g., monkeys, chimpanzees, baboons, etc.), dogs, cats, mice, hamsters,rats, horses, cows, pigs, rabbits, sheep and goats. Avian subjects mayinclude, but are not limited to, chickens, turkeys, ducks, geese, quailand pheasant, and birds kept as pets (e.g., parakeets, parrots, macaws,cockatoos, and the like). In particular embodiments, the subject is froman endangered species. In particular embodiments, the subject is alaboratory animal. Human subjects may include neonates, infants,juveniles, adults, and geriatric subjects. In particular embodiments,the subject is male. In particular embodiments, the subject is female.

As used herein, the term “therapeutically effective” refers to provisionof some improvement or benefit to the subject. Alternatively stated, a“therapeutically effective amount” is an amount that will provide somealleviation, mitigation, or decrease in at least one clinical symptom inthe subject (e.g., in the case of cancer, reduced tumor size, decreasedincidence of metastasis, etc.). Those skilled in the art will appreciatethat the therapeutic effects need not be complete or curative, as longas some benefit is provided to the subject.

As used herein, the terms “therapeutically effective amount” and“therapeutically acceptable amount” (and grammatical variants thereof)refer to an amount that will elicit a therapeutically useful response ina subject. The therapeutically useful response may provide somealleviation, mitigation, or decrease in at least one clinical symptom inthe subject. The terms also include an amount that will prevent or delayat least one clinical symptom in the subject and/or reduce and/or delaythe severity of the onset of a clinical symptom in a subject relative towhat would occur in the absence of the methods of the invention. Thoseskilled in the art will appreciate that the therapeutically usefulresponse need not be complete or curative or prevent permanently, aslong as some benefit is provided to the subject.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, inhibiting the progressof or preventing a disease or disorder. In some embodiments, treatmentmay be administered after one or more symptoms have developed. In otherembodiments, treatment may be administered in the absence of symptoms.For example, treatment may be administered to a susceptible individualprior to the onset of symptoms (e.g., in light of a history of symptomsand/or in light of genetic or other susceptibility factors). Treatmentmay also be continued after symptoms have resolved, for example, toprevent or delay their recurrence.

As used herein, the term “treatment effective amount” (and grammaticalvariants thereof) refers to an amount that is sufficient to provide someimprovement or benefit to the subject. Alternatively stated, a“treatment effective amount” is an amount that will provide somealleviation, mitigation, decrease, or stabilization in at least oneclinical symptom in the subject. Those skilled in the art willappreciate that the therapeutic effects need not be complete orcurative, as long as some benefit is provided to the subject.

The present invention provides compositions useful for the preventionand/or treatment of disease.

In some embodiments, the present invention provides a compound ofFormula I

or a pharmaceutically acceptable salt or prodrug thereof, wherein E is—C—, —O—, —S— or is absent; each of R_(A) and R_(C) is independently —Hor —OH; each of R_(B) and R_(D) is independently —H, —OH or —O—C₁₋₆alkyl; and R_(E) is —OH or O—C₁₋₆ acyl. In some such embodiments, E is—O—; each of R_(A) and R_(C) is independently —H or —OH; each of R_(D)and R_(B) is independently —H, —OH or —O—C₁₋₆ alkyl; and R_(E) is —H,—OH or —O—C₁₋₆ acyl. In some such embodiments, one of R_(B) and R_(D) is—H and the other is —OH or —O—C₁₋₆ alkyl. In some such embodiments,R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, one of R_(B) and R_(D) is —H and the other is —OH or—O—C₁₋₆alkyl; and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or—O—C(O)-Bu. In some such embodiments, E is —C—; one of R_(B) and R_(D)is —H and the other is —OH or —O—C₁₋₆ alkyl; and R_(E) is —OH,—O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some suchembodiments, E is —O—; one of R_(B) and R_(D) is —H and the other is —OHor —O—C₁₋₆ alkyl; and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr,or —O—C(O)-Bu. In some such embodiments, E is absent; one of R_(B) andR_(D) is —H and the other is —OH or —O—C₁₋₆alkyl; and R_(E) is —OH,—O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some suchembodiments, one of R_(B) and R_(D) is —H and the other is —OH, —OMe,—OEt, —OPr, or —OBu. In some such embodiments, R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is —C—; one of R_(B) and R_(D) is —H and the otheris —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is —O—; one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is absent; one of R_(B) and R_(D) is —H and theother is —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments,R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are —OH. In somesuch embodiments, at least two of R_(B), R_(C) and R_(D) are —OH. Insome such embodiments, E is —C— and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O— and at least two ofR_(B), R_(C) and R_(D) are —OH. In some such embodiments, E is absentand at least two of R_(B), R_(C) and R_(D) are —OH. In some suchembodiments, E is —C—; R_(E) is —OH and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O—; R_(E) is —OH and atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments, Eis absent; R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are—OH. In some such embodiments, neither R_(B) nor R_(D) is —OMe. In somesuch embodiments, each of R_(B) and R_(D) is independently —H, —OH. Insome such embodiments, R_(E) is —O—C(O)-Me. In some such embodiments,each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —C—; each of R_(B) and R_(D)is independently —H, —OH, or —OMe; and R_(E) is —O—C(O)-Me. In some suchembodiments, E is —O—; each of R_(B) and R_(D) is independently —H, —OH,or —OMe; and R_(E) is —O—C(O)-Me. In some such embodiments, E is absent;each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —O— and R_(A) is —OH. In somesuch embodiments, E is —O— and R_(A) is —H.

In some embodiments, the present invention provides a compound ofFormula IA

or a pharmaceutically acceptable salt or prodrug thereof, wherein E is—C—, —O—, —S— or is absent; each of R_(A) and R_(C) is independently —Hor —OH; each of R_(B) and R_(D) is independently —H, —OH or—O—C₁₋₆alkyl; and R_(E) is —OH or O—C₁₋₆ acyl. In some such embodiments,E is —O—; each of R_(A) and R_(C) is independently —H or —OH; each ofR_(D) and R_(B) is independently —H, —OH or —O—C₁₋₆alkyl; and R_(E) is—H, —OH or —O—C₁₋₆ acyl. In some such embodiments, one of R_(B) andR_(D) is —H and the other is —OH or —O—C₁₋₆alkyl. In some suchembodiments, R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or—O—C(O)-Bu. In some such embodiments, one of R_(B) and R_(D) is —H andthe other is —OH or —O—C₁₋₆ alkyl; and R_(E) is —OH, —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is—C—; one of R_(B) and R_(D) is —H and the other is —OH or —O—C₁₋₆alkyl;and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. Insome such embodiments, E is —O—; one of R_(B) and R_(D) is —H and theother is —OH or —O—C₁₋₆ alkyl; and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is absent; one ofR_(B) and R_(D) is —H and the other is —OH or —O—C₁₋₆alkyl; and R_(E) is—OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some suchembodiments, one of R_(B) and R_(D) is —H and the other is —OH, —OMe,—OEt, —OPr, or —OBu. In some such embodiments, R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is —C—; one of R_(B) and R_(D) is —H and the otheris —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is —O—; one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is absent; one of R_(B) and R_(D) is —H and theother is —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments,R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are —OH. In somesuch embodiments, at least two of R_(B), R_(C) and R_(D) are —OH. Insome such embodiments, E is —C— and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O— and at least two ofR_(B), R_(C) and R_(D) are —OH. In some such embodiments, E is absentand at least two of R_(B), R_(C) and R_(D) are —OH. In some suchembodiments, E is —C—; R_(E) is —OH and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O—; R_(E) is —OH and atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments, Eis absent; R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are—OH. In some such embodiments, neither R_(B) nor R_(D) is —OMe. In somesuch embodiments, each of R_(B) and R_(D) is independently —H, —OH. Insome such embodiments, R_(E) is —O—C(O)-Me. In some such embodiments,each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —C—; each of R_(B) and R_(D)is independently —H, —OH, or —OMe; and R_(E) is —O—C(O)-Me. In some suchembodiments, E is —O—; each of R_(B) and R_(D) is independently —H, —OH,or —OMe; and R_(E) is —O—C(O)-Me. In some such embodiments, E is absent;each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —O— and R_(A) is —OH. In somesuch embodiments, E is —O— and R_(A) is —H.

In some embodiments, the present invention provides a compound ofFormula IB

or a pharmaceutically acceptable salt or prodrug thereof, wherein E is—C—, —O—, —S— or is absent; each of R_(A) and R_(C) is independently —Hor —OH; each of R_(B) and R_(D) is independently —H, —OH or—O—C₁₋₆alkyl; and R_(E) is —OH or O—C₁₋₆ acyl. In some such embodiments,E is —O—; each of R_(A) and R_(C) is independently —H or —OH; each ofR_(D) and R_(B) is independently —H, —OH or —O—C₁₋₆ alkyl; and R_(E) is—H, —OH or —O—C₁₋₆ acyl. In some such embodiments, one of R_(B) andR_(D) is —H and the other is —OH or —O—C₁₋₆ alkyl. In some suchembodiments, R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or—O—C(O)-Bu. In some such embodiments, one of R_(B) and R_(D) is —H andthe other is —OH or —O—C₁₋₆alkyl; and R_(E) is —OH, —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is—C—; one of R_(B) and R_(D) is —H and the other is —OH or —O—C₁₋₆ alkyl;and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. Insome such embodiments, E is —O—; one of R_(B) and R_(D) is —H and theother is —OH or —O—C₁₋₆alkyl; and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is absent; one ofR_(B) and R_(D) is —H and the other is —OH or —O—C₁₋₆alkyl; and R_(E) is—OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some suchembodiments, one of R_(B) and R_(D) is —H and the other is —OH, —OMe,—OEt, —OPr, or —OBu. In some such embodiments, R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is —C—; one of R_(B) and R_(D) is —H and the otheris —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is —O—; one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is absent; one of R_(B) and R_(D) is —H and theother is —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments,R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are —OH. In somesuch embodiments, at least two of R_(B), R_(C) and R_(D) are —OH. Insome such embodiments, E is —C— and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O— and at least two ofR_(B), R_(C) and R_(D) are —OH. In some such embodiments, E is absentand at least two of R_(B), R_(C) and R_(D) are —OH. In some suchembodiments, E is —C—; R_(E) is —OH and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O—; R_(E) is —OH and atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments, Eis absent; R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are—OH. In some such embodiments, neither R_(B) nor R_(D) is —OMe. In somesuch embodiments, each of R_(B) and R_(D) is independently —H, —OH. Insome such embodiments, R_(E) is —O—C(O)-Me. In some such embodiments,each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —C—; each of R_(B) and R_(D)is independently —H, —OH, or —OMe; and R_(E) is —O—C(O)-Me. In some suchembodiments, E is —O—; each of R_(B) and R_(D) is independently —H, —OH,or —OMe; and R_(E) is —O—C(O)-Me. In some such embodiments, E is absent;each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —O— and R_(A) is —OH. In somesuch embodiments, E is —O— and R_(A) is —H.

In some embodiments, the present invention provides a compound ofFormula II

or a pharmaceutically acceptable salt or prodrug thereof, wherein eachof R_(B) and R_(D) is independently —H, —OH or —O—C₁₋₆ alkyl; and R_(E)is —O—C(O)-Me. In some such embodiments, each of R_(B) and R_(D) isindependently —OH or —O—C₁₋₆alkyl. In some such embodiments, each ofR_(B) and R_(D) is —OH. In some such embodiments, each of R_(B) andR_(D) is —O—C₁₋₆alkyl. In some such embodiments, each of R_(B) and R_(D)is independently —O—C₁₋₃ alkyl. In some such embodiments, each of R_(B)and R_(D) is —O—C₁₋₃alkyl. In some such embodiments, each of R_(B) andR_(D) is —O-Me. In some such embodiments, neither R_(B) nor R_(D) is—OMe. In some such embodiments, one of R_(B) and R_(D) is —OH and theother is —O—C₁₋₆ alkyl. In some such embodiments, one of R_(B) and R_(D)is —OH and the other is —OMe, —OEt, —OPr, or —OBu. In some suchembodiment each of R_(B) and R_(D) independently is —OH, —OMe, —OEt,—OPr, or —OBu. In some such embodiments each of R_(B) and R_(D)independently is —OH, —OMe or —OEt.

In some embodiments, the present invention provides a compound ofFormula III

or a pharmaceutically acceptable salt or prodrug thereof, wherein R_(A)is —H or —OH; R_(C) is —H, —OH, or —O—C₁₋₆ alkyl; and R_(E) is —OH orO—C₁₋₆ acyl. In some such embodiments, R_(C) is —H, —OH, —OMe, —OEt,—OPr, or —OBu. In some such embodiments, R_(E) is —OH or O—C₁₋₃ acyl. Insome such embodiments, R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr,or —O—C(O)-Bu. In some such embodiments, each of R_(A) and R_(C) is —OH.In some such embodiments, each of R_(A) and R_(E) is —OH. In some suchembodiments, each of R_(C) and R_(E) is —OH. In some such embodiments,R_(A) is —OH; R_(C) is —H or —OH; and R_(E) is —OH or —O—C₁₋₆ acyl. Insome such embodiments, R_(A) is —OH; R_(C) is —H or —OH; and R_(E) is—OH or O—C₁₋₃ acyl. In some such embodiments, R_(E) is —O—C(O)-Me. Insome such embodiments, R_(C) is —OH and R_(E) is —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, —O—C(O)-Bu. In some such embodiments, R_(C) is —OH and R_(E)is —O—C(O)-Me. In some embodiments, each of R_(A) and R_(C) is —OH andR_(E) is —O—C(O)Me. In some such embodiments, R_(A) is —OH; R_(C) is —H,—OH, —OMe, —OEt, —OPr, or —OBu and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, R_(A) is —H; R_(C)is —OH, or —O—C₁₋₆ alkyl; and R_(E) is —OH or —O—C₁₋₆ acyl. In some suchembodiments, R_(A) is —H; R_(C) is —OH, —OMe, —OEt, —OPr, or —OBu; andR_(E) is —OH or —O—C₁₋₆ acyl.

In some embodiments, the present invention provides a compound ofFormula IV

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the present invention provides a compound ofFormula V

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the present invention provides a compound ofFormula VI

or a pharmaceutically acceptable salt or prodrug thereof, wherein R_(E)is —H, —OH, or —O—C₁₋₆ acyl; R_(F) is optionally substituted C₁₋₁₂ alkylor optionally substituted C₁₋₁₂ alkenyl; and R_(G) is —H or C₁₋₆alkyl.In some such embodiments, R_(E) is —O—C(O)—C₁₋₁₂ alkyl. In some suchembodiments, R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or—O—C(O)-Bu. In some such embodiments, R_(G) is —H or —Me. In some suchembodiments, R_(E) is —O—C(O)-Me and R_(G) is —Me. In some suchembodiments, R_(F) is optionally substituted C₁₋₉alkyl or optionallysubstituted C₁₋₉ alkenyl. In some such embodiments, R_(F) is optionallysubstituted C₁₋₇ alkyl or optionally substituted C₁₋₇ alkenyl. In somesuch embodiments, R_(F) is

wherein n=3, 5, or 7. In some such embodiments, R_(F) is optionallysubstituted C₂₋₇alkyl or optionally substituted C₂₋₇ alkenyl. In somesuch embodiments, R_(F) is optionally substituted C₂₋₉ alkyl oroptionally substituted C₂₋₉ alkenyl. In some such embodiments, R_(F) isoptionally substituted C₂₋₁₁ alkyl or optionally substituted C₂₋₁₁alkenyl. In some embodiments R_(G) is —Me; R_(E) is —OH or —O—C(O)-Me;and R_(F) is optionally substituted C₂₋₇alkyl or optionally substitutedC₂₋₇alkenyl. In some such embodiments, R_(G) is —H or —Me; R_(E) is —OH,—O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu; and R_(F) is:

wherein n=3, 5, or 7; in some variations, n=3; in some variations n=5;in some variations n=7.

In some embodiments, the present invention provides a compound ofFormula VII

or a pharmaceutically acceptable salt or prodrug thereof, wherein R_(F)is optionally substituted C₁₋₁₂ alkyl or optionally substituted C₁₋₁₂alkenyl. In some such embodiments, R_(F) is optionally substituted C₁₋₉alkyl or optionally substituted C₁₋₉alkenyl. In some such embodiments,R_(F) is optionally substituted C₁₋₇alkyl or optionally substituted C₁₋₇alkenyl. In some such embodiments, R_(F) is optionally substituted C₂₋₇alkyl or optionally substituted C₂₋₇ alkenyl. In some such embodiments,R_(F) is optionally substituted C₂₋₉alkyl or optionally substitutedC₂₋₉alkenyl. In some such embodiments, R_(F) is optionally substitutedC₂₋₁₁ alkyl or optionally substituted C₂₋₁₁ alkenyl. In someembodiments, R_(F) is optionally substituted C₇ alkyl or optionallysubstituted C₇ alkenyl. In some such embodiments, R_(F) is optionallysubstituted C₉ alkyl or optionally substituted C₉ alkenyl. In some suchembodiments, R_(F) is optionally substituted C₁₁ alkyl or optionallysubstituted C₁₁ alkenyl. In some such embodiments, R_(F) is

wherein n=3, 5, or 7; in some variations, n=3; in some variations n=5;in some variations n=7.

In some embodiments, the present invention provides a compoundcomprising a first moiety and a second moiety, wherein the first andsecond moieties are covalently linked. In some such embodiments, thefirst moiety is aspirin, an aspirin analog or an aspirin derivative. Insome such embodiments, the second moiety is stilbene, an analog orderivative of stilbene, gingerol, an analog or derivative of gingergol,shogaol, an analog or derivative of shogaol, zingerone or an analog orderivative of zingerone. In some such embodiments, the second moiety isnot pterostilbene or an analog or derivative thereof. In some suchembodiments, the second moiety is not an analog or derivative ofpterostilbene. In some such embodiments, the first and second moietiesbehave in a synergistic manner following administration of the compoundto a subject.

Compounds of the present invention may comprise any suitable aspirinderivative or analog, including, but not limited to,

wherein R₅ is —OH or —O—C₁₋₆alkyl. In some embodiments, R₅ is —OMe,—OEt, —OPr, or —OBu.

Compounds of the present invention may comprise any suitable isomer ofstilbene, including (E)-stilbene and (Z)-stilbene.

Compounds of the present invention may comprise any suitable stilbenederivative or analog, including, but not limited to, hydroxylatedderivatives of stilbene such as resveratrol(3,5,4′-trihydroxy-trans-stilbene), pterostilbene(3,5-dimethoxy-4′-hydroxy-E-stilbene), piceatannol(3′,4′,3,5-Tetrahydroxy-trans-stilbene) and pinosylvin(trans-3,5-dihydroxystilbene). In some embodiments, the stilbenederivative or analog is a derivative or analog of resveratrol (e.g.,alkylated resveratrol derivatives and methylated resveratrolderivatives), a derivative or analog of pterostilbene, a derivative oranalog of piceatannol or a derivative or analog of pinosylvin. In someembodiments, the stilbene derivative or analog is an alkylatedresveratrol derivative of Formula VIII

wherein each of R₁ and R₂ independently is —H or a C₁-C₆ carbon chain.In some embodiments, the stilbene derivative or analog is a compound ofFormula IX

wherein each of R₃ and R₄ independently is —H or a C₁-C₆ carbon chain.

Compounds of the present invention may comprise any suitable compoundderived from ginger, including, but not limited to, gingerol, shogaoland zingerone.

Compounds of the present invention may comprise any suitable gingerolderivative or analog, including, but not limited to, 8-gingerol and10-gingerol.

Compounds of the present invention may comprise any suitable shogaolderivative or analog, including, but not limited to, 8-shogaol and10-shogaol.

Compounds of the present invention may comprise any suitable zingeronederivative or analog, including, but not limited to, rheosmin andquinoline derivatives of zingerone.

Compounds of the present invention may be stable in environments havinga pH less than about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0,1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4,2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2,5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6,6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0,8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5,9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7,10.8, 10.9, 11.0, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0,12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2,13.3, 13.4, 13.5, 13.6, 13.7, 13.8 or 14.0. In some embodiments, thecompound is stable in environments having a pH in the range of about 0.0to about 7.0, about 0.0 to about 6.0, about 0.0 to about 5.0, about 0.0to about 4.0, about 0.0 to about 3.5, about 0.0 to about 3.0, about 0.0to about 2.5, about 0.0 to about 2.0, about 0.0 to about 1.5, about 0.0to about 1.0, or about 0.0 to about 0.5. In some embodiments, thecompound is stable in environments having a pH in the range of about 0.5to about 7.0, about 0.5 to about 6.0, about 0.5 to about 5.0, about 0.5to about 4.0, about 0.5 to about 3.5, about 0.5 to about 3.0, about 0.0to about 2.5, about 0.0 to about 2.0, about 0.5 to about 1.5, or about0.5 to about 1.0. In some embodiments, the compound is stable inenvironments having a pH in the range of about 1.0 to about 7.0, about1.0 to about 6.0, about 1.0 to about 5.0, about 1.0 to about 4.0, about1.0 to about 3.5, about 1.0 to about 3.0, about 1.0 to about 2.5, about1.0 to about 2.0, or about 1.0 to about 1.5. In some embodiments, thecompound is stable in environments having a pH in the range of about 1.5to about 7.0, about 1.5 to about 6.0, about 1.5 to about 5.0, about 1.5to about 4.0, about 1.5 to about 3.5, about 1.5 to about 3.0, about 1.0to about 2.5, or about 1.0 to about 2.0. In some embodiments, thecompound is stable in environments having a pH in the range of about 2.0to about 7.0, about 2.0 to about 6.0, about 2.0 to about 5.0, about 2.0to about 4.0, about 2.0 to about 3.5, about 2.0 to about 3.0, or about0.0 to about 2.5. In some embodiments, the compound is stable inenvironments having a pH in the range of about 2.5 to about 7.0, about2.5 to about 6.0, about 2.5 to about 5.0, about 2.5 to about 4.0, about2.5 to about 3.5, or about 2.5 to about 3.0. In some embodiments, thecompound is stable in environments having a pH in the range of about 3.0to about 7.0, about 3.0 to about 6.0, about 3.0 to about 5.0, about 3.0to about 4.0, or about 3.0 to about 3.5. In some embodiments, thecompound is stable in environments having a pH in the range of about 4.0to about 7.0, about 4.0 to about 6.0 about 4.0 to about 5.0. In someembodiments, the compound is stable in environments having a pH in therange of about 5.0 to about 7.0, about 5.0 to about 6.0. In someembodiments, the compound is stable in environments having a pH in therange of about 6.0 to about 7.0. In some embodiments, the compound isstable in gastric fluids.

Compounds of the present invention may be stable in environments havinga pH greater than about 0.0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2,2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6,3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0,5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4,6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8,7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 9.0, 9.1, 9.2, 9.3,9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6,10.7, 10.8, 10.9, 11.0, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9,12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1,13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8 or 13.9.

Compounds of the present invention may not hydrolyze in the stomach.

Compounds of the present invention may be hydrolyzed in vivo toregenerate aspirin (and/or an aspirin derivative or analog) andstilbene/gingerol (and/or a stilbene/gingerol derivative or analog). SeeFIG. 5. Accordingly, compounds of the present invention may serve asprodrugs of aspirin (and aspirin derivatives and analogs) andstilbene/gingerol (and stilbene/gingerol derivatives and analogs).

Compounds of the present invention may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers ordiastereomers. The chemical structures depicted herein are intended toencompass all possible enantiomers and stereoisomers of the illustratedcompounds, including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure)and enantiomeric and stereoisomeric mixtures. As will be understood bythose skilled in the art, enantiomeric and stereoisomeric mixtures canbe resolved into their component enantiomers or stereoisomers using wellknown separation techniques and/or chiral synthesis techniques.

Compounds of the present invention may exist in several tautomericforms, including the enol form, the keto form and mixtures thereof. Thechemical structures depicted herein are intended to encompass allpossible tautomeric forms of the illustrated compounds.

Compounds of the present invention may exist as isotopically labeledcompounds, wherein one or more atoms have an atomic mass different fromthe atomic mass conventionally found in nature. Examples of isotopesthat can be incorporated into the compounds of the present inventioninclude, but are not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P,³²P, ³⁵S, ^(18F) and ³⁶Cl. The chemical structures depicted herein areintended to encompass all possible isotopically labeled versions of thecompounds of the present invention. Isotopically labeled compounds ofthe present invention may be used in any suitable method known in theart, including, but not limited to, methods of preventing, diagnosing,monitoring and/or treating a disorder.

Compounds of the present invention may comprise any suitablepharmaceutically acceptable salt, including, but not limited to, acidaddition salts and base addition salts. Examples of suitable salts canbe found, for example, in STAHL AND WERMUTH, HANDBOOK OF PHARMACEUTICALSALTS PROPERTIES, SELECTION, AND USE, Wiley-VCH, Weinheim, Germany(2002); and Berge et al., Pharmaceutical Salts, J. PHARM. SCI. 66:1-19(1977). In some embodiments, the pharmaceutically acceptable salt is adisalt. In some embodiments, the pharmaceutically acceptable salt is anL-tartrate salt.

Pharmaceutically acceptable acid addition salts include, but are notlimited to, non-toxic salts derived from inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,phosphorus, and the like, as well as the salts derived from organicacids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.Pharmaceutically acceptable acid addition salts thus include theacetate, aspartate, benzoate, besylate (benzenesulfonate),bicarbonate/carbonate, bisulfate, caprylate, camsylate (camphorsulfonate), chlorobenzoate, citrate, edisylate (1,2-ethane disulfonate),dihydrogenphosphate, dinitrobenzoate, esylate (ethane sulfonate),fumarate, gluceptate, gluconate, glucuronate, hibenzate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,isobutyrate, monohydrogen phosphate, isethionate, D-lactate, L-lactate,malate, maleate, malonate, mandelate, mesylate (methanesulfonate),metaphosphate, methylbenzoate, methylsulfate, 2-napsylate (2-naphthalenesulfonate), nicotinate, nitrate, orotate, oxalate, palmoate,phenylacetate, phosphate, phthalate, propionate, pyrophosphate,pyrosulfate, saccharate, sebacate, stearate, suberate, succinatesulfate, sulfite, D-tartrate, L-tartrate, tosylate (toluene sulfonate),and xinafoate salts, and the like of Formulas I, II, III, IV, V, VI, VIIand VIII. Also contemplated are the salts of amino acids such asarginate, gluconate, galacturonate, and the like.

Acid addition salts of Formulas I, II, III, IV, V, VI, VII and VIII maybe prepared by contacting the free form of the basic compound with asufficient amount of the desired acid to produce the salt in theconventional manner. The free form may be regenerated by contacting thesalt form with a base and isolating the free form in the conventionalmanner. The free forms may differ from their respective salt formssomewhat in certain physical properties (e.g., solubility in polarsolvents), but may otherwise be equivalent to their respective saltforms.

Pharmaceutically acceptable base addition salts may be formed withmetals or amines, such as alkali and alkaline earth metal hydroxides, orof organic amines. Examples of metals used as cations are aluminum,calcium, magnesium, potassium, sodium, and the like. Examples ofsuitable amines include arginine, choline, chloroprocaine,N,N′-dibenzylethylenediamine, diethylamine, diethanolamine, diolamine,ethylenediamine (ethane-1,2-diamine), glycine, lysine, meglumine,N-methylglucamine, olamine, procaine (benzathine), and tromethamine.

The base addition salts of Formulas I, II, III, IV, V, VI, VII and VIIImay be prepared by contacting the free form with a sufficient amount ofthe desired base to produce the salt in the conventional manner. Thefree form may be regenerated by contacting the salt form with an acidand isolating the free form in a conventional manner. The free forms maydiffer from their respective salt forms somewhat in certain physicalproperties (e.g., solubility in polar solvents), but may otherwise beequivalent to their respective free salt forms.

Compounds of the present invention may comprise any suitable prodrug,including, but not limited to, esterified forms of Formulas I, II, III,IV, V, VI, VII and VIII.

Compounds of the present invention may possess one or more desirablepharmacokinetic and/or physiological properties. In some embodiments,the compound exhibits improved solubility (e.g., aqueous solubility),absorption, metabolism and/or clinical efficacy (as compared to theindividual moieties that make up the compound, for example).

Compounds of the present invention may have greater and/or moreprolonged therapeutic effects than the individual moieties that make upthe compound. For example, administration of a conjugate compoundcomprising aspirin and gingerol may have a more pronouncedanti-tumorigenesis effect than administration of aspirin and gingerol(and/or administration of an aspirin derivative/analog and a gingerolderivative/analog).

Accordingly, compositions of the present application may achieveadequate anti-tumor efficacy at a lower dose than that required for theindividual moieties that make up the compound.

Compounds of the present invention may have fewer and/or less pronouncedadverse effects (e.g., adverse GI effects associated with theadministration of aspirin) than the individual moieties that make up thecompound. For example, administration of a conjugate compound comprisingan aspirin derivative and a stilbene derivative may produce feweradverse effects than administration of the aspirin derivative and thestilbene derivative (and/or administration of aspirin and stilbenethemselves). The use of a sustained-release formulation for delivery ofthe compound may further reduce any adverse effects.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising, consisting essentially of or consisting of oneor more compounds of the present invention and a pharmaceuticallyacceptable carrier.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising, consisting essentially of or consisting of 1) apharmaceutically acceptable carrier and 2) a compound of Formula I

or a pharmaceutically acceptable salt or prodrug thereof, wherein E is—C—, —O—, —S— or is absent; each of R_(A) and R_(C) is independently —Hor —OH; each of R_(B) and R_(D) is independently —H, —OH or—O—C₁₋₆alkyl; and R_(E) is —OH or O—C₁₋₆ acyl. In some such embodiments,E is —O—; each of R_(A) and R_(C) is independently —H or —OH; each ofR_(D) and R_(B) is independently —H, —OH or —O—C₁₋₆alkyl; and R_(E) is—H, —OH or —O—C₁₋₆ acyl. In some such embodiments, one of R_(B) andR_(D) is —H and the other is —OH or —O—C₁₋₆ alkyl. In some suchembodiments, R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or—O—C(O)-Bu. In some such embodiments, one of R_(B) and R_(D) is —H andthe other is —OH or —O—C₁₋₆ alkyl; and R_(E) is —OH, —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is—C—; one of R_(B) and R_(D) is —H and the other is —OH or —O—C₁₋₆alkyl;and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. Insome such embodiments, E is —O—; one of R_(B) and R_(D) is —H and theother is —OH or —O—C₁₋₆ alkyl; and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is absent; one ofR_(B) and R_(D) is —H and the other is —OH or —O—C₁₋₆alkyl; and R_(E) is—OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some suchembodiments, one of R_(B) and R_(D) is —H and the other is —OH, —OMe,—OEt, —OPr, or —OBu. In some such embodiments, R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is —C—; one of R_(B) and R_(D) is —H and the otheris —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is —O—; one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is absent; one of R_(B) and R_(D) is —H and theother is —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments,R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are —OH. In somesuch embodiments, at least two of R_(B), R_(C) and R_(D) are —OH. Insome such embodiments, E is —C— and at least two of R_(B), R_(C) andR_(D) are —OH, In some such embodiments, E is —O— and at least two ofR_(B), R_(C) and R_(D) are —OH. In some such embodiments, E is absentand at least two of R_(B), R_(C) and R_(D) are —OH. In some suchembodiments, E is —C—; R_(E) is —OH and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O—; R_(E) is —OH and atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments, Eis absent; R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are—OH. In some such embodiments, neither R_(B) nor R_(D) is —OMe. In somesuch embodiments, each of R_(B) and R_(D) is independently —H, —OH. Insome such embodiments, R_(E) is —O—C(O)-Me. In some such embodiments,each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —C—; each of R_(B) and R_(D)is independently —H, —OH, or —OMe; and R_(E) is —O—C(O)-Me. In some suchembodiments, E is —O—; each of R_(B) and R_(D) is independently —H, —OH,or —OMe; and R_(E) is —O—C(O)-Me. In some such embodiments, E is absent;each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —O— and R_(A) is —OH. In somesuch embodiments, E is —O— and R_(A) is —H.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising, consisting essentially of or consisting of 1) apharmaceutically acceptable carrier and 2) a compound of Formula IA

or a pharmaceutically acceptable salt or prodrug thereof, wherein E is—C—, —O—, —S— or is absent; each of R_(A) and R_(C) is independently —Hor —OH; each of R_(B) and R_(D) is independently —H, —OH or —O—C₁₋₆alkyl; and R_(E) is —OH or O—C₁₋₆ acyl. In some such embodiments, E is—O—; each of R_(A) and Re is independently —H or —OH; each of R_(D) andR_(B) is independently —H, —OH or —O—C₁₋₆alkyl; and R_(E) is —H, —OH or—O—C₁₋₆ acyl. In some such embodiments, one of R_(B) and R_(D) is —H andthe other is —OH or —O—C₁₋₆alkyl. In some such embodiments, R_(E) is—OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some suchembodiments, one of R_(B) and R_(D) is —H and the other is —OH or—O—C₁₋₆alkyl; and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or—O—C(O)-Bu. In some such embodiments, E is —C—; one of R_(B) and R_(D)is —H and the other is —OH or —O—C₁₋₆ alkyl; and R_(E) is —OH,—O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some suchembodiments, E is —O—; one of R_(B) and R_(D) is —H and the other is —OHor —O—C₁₋₆alkyl; and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr,or —O—C(O)-Bu. In some such embodiments, E is absent; one of R_(B) andR_(D) is —H and the other is —OH or —O—C₁₋₆alkyl; and R_(E) is —OH,—O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some suchembodiments, one of R_(B) and R_(D) is —H and the other is —OH, —OMe,—OEt, —OPr, or —OBu. In some such embodiments, R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is —C—; one of R_(B) and R_(D) is —H and the otheris —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is —O—; one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is absent; one of R_(B) and R_(D) is —H and theother is —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments,R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are —OH. In somesuch embodiments, at least two of R_(B), R_(C) and R_(D) are —OH. Insome such embodiments, E is —C— and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O— and at least two ofR_(B), R_(C) and R_(D) are —OH. In some such embodiments, E is absentand at least two of R_(B), R_(C) and R_(D) are —OH. In some suchembodiments, E is —C—; R_(E) is —OH and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O—; R_(E) is —OH and atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments, Eis absent; R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are—OH. In some such embodiments, neither R_(B) nor R_(D) is —OMe. In somesuch embodiments, each of R_(B) and R_(D) is independently —H, —OH. Insome such embodiments, R_(E) is —O—C(O)-Me. In some such embodiments,each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —C—; each of R_(B) and R_(D)is independently —H, —OH, or —OMe; and R_(E) is —O—C(O)-Me. In some suchembodiments, E is —O—; each of R_(B) and R_(D) is independently —H, —OH,or —OMe; and R_(E) is —O—C(O)-Me. In some such embodiments, E is absent;each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —O— and R_(A) is —OH. In somesuch embodiments, E is —O— and R_(A) is —H.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising, consisting essentially of or consisting of 1) apharmaceutically acceptable carrier and 2) a compound of Formula IB

or a pharmaceutically acceptable salt or prodrug thereof, wherein E is—C—, —O—, —S— or is absent; each of R_(A) and R_(C) is independently —Hor —OH; each of R_(B) and R_(D) is independently —H, —OH or—O—C₁₋₆alkyl; and R_(E) is —OH or O—C₁₋₆ acyl. In some such embodiments,E is —O—; each of R_(A) and R_(C) is independently —H or —OH; each ofR_(D) and R_(B) is independently —H, —OH or —O—C₁₋₆ alkyl; and R_(E) is—H, —OH or —O—C₁₋₆ acyl. In some such embodiments, one of R_(B) andR_(D) is —H and the other is —OH or —O—C₁₋₆alkyl. In some suchembodiments, R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or—O—C(O)-Bu. In some such embodiments, one of R_(B) and R_(D) is —H andthe other is —OH or —O—C₁₋₆ alkyl; and R_(E) is —OH, —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is—C—; one of R_(B) and R_(D) is —H and the other is —OH or —O—C₁₋₆alkyl;and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. Insome such embodiments, E is —O—; one of R_(B) and R_(D) is —H and theother is —OH or —O—C₁₋₆alkyl; and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is absent; one ofR_(B) and R_(D) is —H and the other is —OH or —O—C₁₋₆alkyl; and R_(E) is—OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some suchembodiments, one of R_(B) and R_(D) is —H and the other is —OH, —OMe,—OEt, —OPr, or —OBu. In some such embodiments, R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is —C—; one of R_(B) and R_(D) is —H and the otheris —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is —O—; one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is absent; one of R_(B) and R_(D) is —H and theother is —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, atleast two of R_(B), Re and R_(D) are —OH. In some such embodiments,R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are —OH. In somesuch embodiments, at least two of R_(B), Re and R_(D) are —OH. In somesuch embodiments, E is —C— and at least two of R_(B), Re and R_(D) are—OH. In some such embodiments, E is —O— and at least two of R_(B), Reand R_(D) are —OH. In some such embodiments, E is absent and at leasttwo of R_(B), R_(C) and R_(D) are —OH. In some such embodiments, E is—C—; R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are —OH. Insome such embodiments, E is —O—; R_(E) is —OH and at least two of R_(B),R_(C) and R_(D) are —OH. In some such embodiments, E is absent; R_(E) is—OH and at least two of R_(B), R_(C) and R_(D) are —OH. In some suchembodiments, neither R_(B) nor R_(D) is —OMe. In some such embodiments,each of R_(B) and R_(D) is independently —H, —OH. In some suchembodiments, R_(E) is —O—C(O)-Me. In some such embodiments, each ofR_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —C—; each of R_(B) and R_(D)is independently —H, —OH, or —OMe; and R_(E) is —O—C(O)-Me. In some suchembodiments, E is —O—; each of R_(B) and R_(D) is independently —H, —OH,or —OMe; and R_(E) is —O—C(O)-Me. In some such embodiments, E is absent;each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —O— and R_(A) is —OH. In somesuch embodiments, E is —O— and R_(A) is —H.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising, consisting essentially of or consisting of 1) apharmaceutically acceptable carrier and 2) a compound of Formula II

or a pharmaceutically acceptable salt or prodrug thereof, wherein eachof R_(B) and R_(D) is independently —OH or —O—C₁₋₆alkyl; and R_(E) is—O—C(O)-Me. In some such embodiments, each of R_(B) and R_(D) isindependently —OH or —O—C₁₋₆ alkyl. In some such embodiments, each ofR_(B) and R_(D) is —OH. In some such embodiments, each of R_(B) andR_(D) is —O—C₁₋₆alkyl. In some such embodiments, each of R_(B) and R_(D)is independently —O—C₁₋₃alkyl. In some such embodiments, each of R_(B)and R_(D) is —O—C₁₋₃alkyl. In some such embodiments, each of R_(B) andR_(D) is —O-Me. In some such embodiments, neither R_(B) nor R_(D) is—OMe. In some such embodiments, one of R_(B) and R_(D) is —OH and theother is —O—C₁₋₆ alkyl. In some such embodiments, one of R_(B) and R_(D)is —OH and the other is —OMe, —OEt, —OPr, or —OBu. In some suchembodiment each of R_(B) and R_(D) independently is —OH, —OMe, —OEt,—OPr, or —OBu. In some such embodiments each of R_(B) and R_(D)independently is —OH, —OMe or —OEt.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising, consisting essentially of or consisting of 1) apharmaceutically acceptable carrier and 2) a compound of Formula III

or a pharmaceutically acceptable salt or prodrug thereof, wherein R_(A)is —H or —OH; R_(C) is —H, —OH, or —O—C₁₋₆alkyl; and R_(E) is —OH orO—C₁₋₆ acyl. In some such embodiments, R_(C) is —H, —OH, —OMe, —OEt,—OPr, or —OBu. In some such embodiments, R_(E) is —OH or O—C₁₋₃ acyl. Insome such embodiments, R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr,or —O—C(O)-Bu. In some such embodiments, each of R_(A) and R_(C) is —OH.In some such embodiments, each of R_(A) and R_(E) is —OH. In some suchembodiments, each of R_(C) and R_(E) is —OH. In some such embodiments,R_(A) is —OH; R_(C) is —H or —OH; and R_(E) is —OH or —O—C₁₋₆ acyl. Insome such embodiments, R_(A) is —OH; R_(C) is —H or —OH; and R_(E) is—OH or O—C₁₋₃ acyl. In some such embodiments, R_(E) is —O—C(O)-Me. Insome such embodiments, R_(C) is —OH and R_(E) is —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, —O—C(O)-Bu. In some such embodiments, R_(C) is —OH and R_(E)is —O—C(O)-Me. In some embodiments, each of R_(A) and R_(C) is —OH andR_(E) is —O—C(O)Me. In some such embodiments, R_(A) is —OH; R_(C) is —H,—OH, —OMe, —OEt, —OPr, or —OBu and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, R_(A) is —H; R_(C)is —OH, or —O—C₁₋₆alkyl; and R_(E) is —OH or —O—C₁₋₆ acyl. In some suchembodiments, R_(A) is —H; R_(C) is —OH, —OMe, —OEt, —OPr, or —OBu; andR_(E) is —OH or —O—C₁₋₆ acyl.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising, consisting essentially of or consisting of 1) apharmaceutically acceptable carrier and 2) a compound of Formula IV

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising, consisting essentially of or consisting of I) apharmaceutically acceptable carrier and 2) a compound of Formula V

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising, consisting essentially of or consisting of 1) apharmaceutically acceptable carrier and 2) a compound of Formula VI

or a pharmaceutically acceptable salt or prodrug thereof, wherein R_(E)is —H, —OH, or —O—C₁₋₆ acyl; R_(F) is optionally substituted C₁₋₁₂ alkylor optionally substituted C₁₋₁₂ alkenyl; and R_(G) is —H or C₁₋₆ alkyl.In some such embodiments, R_(E) is —O—C(O)—C₁₋₁₂ alkyl. In some suchembodiments, R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or—O—C(O)-Bu. In some such embodiments, R_(G) is —H or —Me. In some suchembodiments, R_(E) is —O—C(O)-Me and R_(G) is —Me. In some suchembodiments, R_(F) is optionally substituted C₁₋₉alkyl or optionallysubstituted C₁₋₉alkenyl. In some such embodiments, R_(F) is optionallysubstituted C₁₋₇alkyl or optionally substituted C₁₋₇alkenyl. In somesuch embodiments, R_(F) is

wherein n=3, 5, or 7. In some such embodiments, R_(F) is optionallysubstituted C₂₋₇alkyl or optionally substituted C₂₋₇alkenyl. In somesuch embodiments, R_(F) is optionally substituted C₂₋₉alkyl oroptionally substituted C₂₋₉ alkenyl. In some such embodiments, R_(F) isoptionally substituted C₂₋₁₁ alkyl or optionally substituted C₂₋₁₁alkenyl. In some embodiments R_(G) is —Me; R_(E) is —OH or —O—C(O)-Me;and R_(F) is optionally substituted C₂₋₇alkyl or optionally substitutedC₂₋₇ alkenyl. In some such embodiments, R_(G) is —H or —Me; R_(E) is—OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu; and R_(F) is:

wherein n=3, 5, or 7; in some variations, n=3; in some variations n=5;in some variations n=7.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising, consisting essentially of or consisting of 1) apharmaceutically acceptable carrier and 2) a compound of Formula VII

or a pharmaceutically acceptable salt or prodrug thereof, wherein R_(F)is optionally substituted C₁₋₁₂ alkyl or optionally substituted C₁₋₁₂alkenyl. In some such embodiments, R_(F) is optionally substitutedC₁₋₉alkyl or optionally substituted C₁₋₉ alkenyl. In some suchembodiments, R_(F) is optionally substituted C₁₋₇alkyl or optionallysubstituted C₁₋₇alkenyl. In some such embodiments, R_(F) is optionallysubstituted C₂₋₇alkyl or optionally substituted C₂₋₇ alkenyl. In somesuch embodiments, R_(F) is optionally substituted C₂₋₉alkyl oroptionally substituted C₂₋₉alkenyl. In some such embodiments, R_(F) isoptionally substituted C₂₋₁₁ alkyl or optionally substituted C₂₋₁₁alkenyl. In some embodiments, R_(F) is optionally substituted C₇ alkylor optionally substituted C₇ alkenyl. In some such embodiments, R_(F) isoptionally substituted C₉ alkyl or optionally substituted C₉ alkenyl. Insome such embodiments, R_(F) is optionally substituted C₁₁ alkyl oroptionally substituted C₁ alkenyl. In some such embodiments, R_(F) is

wherein n=3, 5, or 7; in some variations, n=3; in some variations n=5;in some variations n=7.

The concentration of the compound(s) in the pharmaceutical compositionmay vary widely (i.e., from less than about 0.05% to about 90% or moreby weight) in accordance with the particular mode of administration, thedisease(s)/disorder(s)/symptom(s) being treated, the age/weight of thesubject, etc.

In some such embodiments, the pharmaceutical composition comprises aunit dose comprising, consisting essentially of or consisting of acompound of the present invention and a pharmaceutically acceptablecarrier. The unit dose may be from about 0.5 to about 500 mg/kg, about0.5 to about 450 mg/kg, about 0.5 to about 400 mg/kg, about 0.5 to about350 mg/kg, about 0.5 to about 300 mg/kg, about 0.5 to about 250 mg/kg,about 0.5 to about 200 mg/kg, about 0.5 to about 150 mg/kg, about 0.5 toabout 100 mg/kg, about 0.5 to about 50 mg/kg, about 0.5 to about 25mg/kg, about 0.5 to about 20 mg/kg, about 0.5 to about 15 mg/kg, about0.5 to about 10 mg/kg, about 0.5 to about 5 mg/kg; about 1 to about 500mg/kg, about 1 to about 450 mg/kg, about 1 to about 400 mg/kg, about 1to about 350 mg/kg, about 1 to about 300 mg/kg, about 1 to about 250mg/kg, about 1 to about 200 mg/kg, about 1 to about 150 mg/kg, about 1to about 100 mg/kg, about 1 to about 50 mg/kg, about 1 to about 25mg/kg, about 1 to about 20 mg/kg, about 1 to about 15 mg/kg, about 1 toabout 10 mg/kg, about 1 to about 5 mg/kg, about 2 to about 500 mg/kg,about 2 to about 450 mg/kg, about 2 to about 400 mg/kg, about 2 to about350 mg/kg, about 2 to about 300 mg/kg, about 2 to about 250 mg/kg, about2 to about 200 mg/kg, about 2 to about 150 mg/kg, about 2 to about 100mg/kg, about 2 to about 50 mg/kg, about 2 to about 25 mg/kg, about 2 toabout 20 mg/kg, about 2 to about 15 mg/kg, about 2 to about 10 mg/kg,about 2 to about 5 mg/kg, 3 to about 500 mg/kg, about 3 to about 450mg/kg, about 3 to about 400 mg/kg, about 3 to about 350 mg/kg, about 3to about 300 mg/kg, about 3 to about 250 mg/kg, about 3 to about 200mg/kg, about 3 to about 150 mg/kg, about 3 to about 100 mg/kg, about 3to about 50 mg/kg, about 3 to about 25 mg/kg, about 3 to about 20 mg/kg,about 3 to about 15 mg/kg, about 3 to about 10 mg/kg, or about 3 toabout 5 mg/kg of a composition of the present invention (e.g., acompound of the present invention). In some embodiments, the unit doseis at least about 1 μg/kg, 2 μg/kg, 3 μg/kg, 4 μg/kg, 5 μg/kg, 10 μg/kg,15 μg/kg, 20 μg/kg, 30 μg/kg, 40 μg/kg, 50 μg/kg, 60 μg/kg, 70 μg/kg, 80μg/kg, 90 μg/kg, 100 μg/kg, 150 μg/kg, 200 μg/kg, 250 μg/kg, 300 μg/kg,350 μg/kg, 400 μg/kg, 450 μg/kg, 500 μg/kg, 550 μg/kg, 600 μg/kg, 650μg/kg, 700 μg/kg, 750 μg/kg, 800 μg/kg, 850 μg/kg, 900 μg/kg, 950 μg/kg,1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90mg/kg, 95 mg/kg, 100 mg/kg, 110 mg/kg, 120 mg/kg, 130 mg/kg, 140 mg/kg,150 mg/kg, 160 mg/kg, 170 mg/kg, 180 mg/kg, 190 mg/kg, 200 mg/kg, 250mg/kg, 300 mg/kg, 350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 1000 mg/kgor more of a composition of the present invention (e.g., a compound ofthe present invention).

Pharmaceutical compositions of the present invention may comprise anysuitable pharmaceutical carrier moiety, including, but not limited to,phosphate buffered saline and isotonic saline solution. Other examplesof pharmaceutically acceptable carriers may be found, for example, inANSEL'S PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS (9th Ed.,Lippincott Williams and Wilkins (2010)), PHARMACEUTICAL SCIENCES (18thEd., Mack Publishing Co. (1990) or REMINGTON: THE SCIENCE AND PRACTICEOF PHARMACY (21st Ed., Lippincott Williams & Wilkins (2005)).

Pharmaceutical compositions of the present invention may comprise anysuitable diluent or excipient, including, but not limited to, those setforth in ANSEL'S PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS(9th Ed., Lippincott Williams and Wilkins (2010)), HANDBOOK OFPHARMACEUTICAL EXCIPIENTS (6th Ed., American Pharmaceutical Association(2009)) and REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (21st Ed.,Lippincott Williams & Wilkins (2005)). In some embodiments, thecomposition comprises one or more pharmaceutically acceptable diluentsand/or one or more pharmaceutically acceptable excipients.

Pharmaceutical compositions of the present invention may comprise anysuitable auxiliary substance, including, but not limited to, pHadjusting and/or buffering agents, tonicity adjusting and/or bufferingagents and lipid-protective agents that protect lipids againstfree-radical and lipid-peroxidative damages (e.g., alpha-tocopherol andwater-soluble iron-specific chelators, such as ferrioxamine).

Pharmaceutical compositions of the present invention may comprise atleast one supplemental agent. In some embodiments, the at least onesupplemental agent comprises another compound of the present invention.In some embodiments, the at least one supplemental agent comprises anantitumor alkylating agent, an antitumor antimetabolite, an antitumorantibiotics, a plant-derived antitumor agent, an antitumororganoplatinum compound, an antitumor campthotecin derivative, anantitumor tyrosine kinase inhibitor, a monoclonal antibody, aninterferon, a biological response modifier, a hormonal anti-tumor agent,an angiogenesis inhibitor, a differentiating agent or a pharmaceuticallyacceptable salt or prodrug of any of the foregoing.

Pharmaceutical compositions of the present invention may be in any formsuitable for the intended method of administration and may be preparedaccording to any suitable method.

Pharmaceutical compositions for oral use may be presented as tablets,troches, lozenges, aqueous or oil suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, syrups and/or elixirs. Suchcompositions may comprise one or more sweetening agents, flavoringagents, coloring agents and/or preserving agents.

Formulation for oral use may be tablets containing a compound of thepresent invention in admixture with one or more pharmaceuticallyacceptable excipients. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets may be uncoated or may be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be presented as hard gelatin capsuleswhere the compound of the present invention is mixed with an inert soliddiluent, for example calcium phosphate or kaolin, or as soft gelatincapsules wherein the compound of the present invention is mixed withwater or an oil medium, such as peanut oil, liquid paraffin or olive oil

Aqueous suspensions of the application contain the compound of thepresent invention in admixture with excipients suitable for themanufacture of aqueous suspensions. Such excipients include a suspendingagent, such as sodium carboxymethylcellulose, methylcellulose,hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia, and dispersing or wetting agents such as anaturally occurring phosphatide (e.g., lecithin), a condensation productof an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),a condensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethyleneoxycetanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension may also contain one or more preservatives such asethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, oneor more flavoring agents and one or more sweetening agents, such assucrose or saccharin.

Oil suspensions may be formulated by suspending the compound of thepresent invention in a vegetable oil, such as arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oral suspensions may contain a thickening agent, such as beeswax,hard paraffin or cetyl alcohol. Sweetening agents, such as those setforth above, and flavoring agents may be added to provide a palatableoral preparation. These compositions may be preserved by the addition ofan antioxidant such as ascorbic acid.

Dispersible powders and granules of the application suitable forpreparation of an aqueous suspension by the addition of water providethe compound of the present invention in admixture with a dispersing orwetting agent, a suspending agent, and one or more preservatives.Suitable dispersing or wetting agents and suspending agents areexemplified by those disclosed above. Additional excipients, for examplesweetening, flavoring and coloring agents, may also be present.

Pharmaceutical compositions of the present invention may be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, such asglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative, a flavoring or a coloring agent.

Pharmaceutical compositions of the present invention may be in the formof a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

As noted above, formulations of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion ora water-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in a freeflowing form such as a powder or granules, optionally mixed with abinder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (e.g., sodiumstarch glycolate, cross-linked povidone, cross-linked sodiumcarboxymethyl cellulose) surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered compound moistened with an inert liquid diluent. The tabletsmay optionally be coated or scored and may be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropyl methylcellulose in varying proportionsto provide the desired release profile. Tablets may optionally beprovided with an enteric coating, to provide release in parts of the gutother than the stomach.

Pharmaceutical compositions of the present invention may be inimmediate-release formulations. A variety of known methods and materialsmay be used to bring about the immediate release. For instance, placingthe compound of the present invention along an exterior of a tablet(e.g., coating the exterior or formulating the outer layer with theagent) and/or combined with forming a tablet by compressing the powderusing low compaction can produce immediate-release of the compound ofthe present invention from the composition.

Pharmaceutical compositions of the present invention may be incontrolled-release and/or sustained-release formulations. Pharmaceuticalcompositions of the present invention may comprise one or more carriersthat protect the compound of the present invention against rapidelimination from the body, such as time-release formulations orcoatings. Such carriers include controlled-release formulations,including, for example, microencapsulated delivery systems. Compounds ofthe present invention can be included in the pharmaceutically acceptablecarrier in amounts sufficient to treat an individual. Thecontrolled-release form can be in an amount that is effective to protectthe compound of the present invention from rapid elimination from thebody, or to provide a sustained release or dosage, such as between about1 μg/kg/min to about 500 μg/kg/min, or alternately between about 2μg/kg/min to about 250 μg/kg/min. Generally the controlled releasedosage form provides less than 100 μg/kg/min, less than 50 μg/kg/min oreven less than 10 μg/kg/min.

In some embodiments, the pharmaceutical composition is in oral dosageform and comprises a matrix that includes a controlled-release material.In certain embodiments, the matrix is compressible into a tablet and canbe optionally overcoated with a coating that can control the release ofthe compound of the present invention from the composition. In thisembodiment, the compound of the present invention is maintained within atherapeutic range over an extended period of time. In certain alternateembodiments, the matrix is encapsulated.

Tablets or capsules containing a composition of the present applicationcan be coated or otherwise compounded to provide a dosage form affordingthe advantage of prolonged action. For example, the tablet or capsulecan contain an inner dosage and an outer dosage component, the latterbeing in the form of an envelope over the former. The two components canbe separated by an enteric layer that serves to resist disintegration inthe stomach and permit the inner component to pass intact into theduodenum or to be delayed in release. For controlled extended release,the capsule can also have micro drilled holes.

A coating comprising an initial dose or first dose of a compound of thepresent invention in immediate-release form can be added to the outsideof a controlled-release tablet core comprising a second dose of acompound of the present invention to produce a final dosage form. Such acoating can be prepared by admixing the first dosage withpolyvinylpyrrolidone (PVP) 29/32 or hydroxypropyl methylcellulose (HPMC)and water/isopropyl alcohol and triethyl acetate. Such animmediate-release coating can be spray coated onto the tablet cores. Theimmediate-release coating can also be applied using a press-coatingprocess with a blend consisting of 80% by weight promethazine and 20% byweight of lactose and hydroxypropyl methylcellulose type 2910.Press-coating techniques are known in the art.

The immediate-release or controlled-release dosage forms of the presentinvention can also take the form of a multilayer tablet, such as abi-layered tablet, which comprises a first layer and a second layer. Ina further aspect of the bi-layered tablet, the first layer is animmediate release layer and/or the second layer is a controlled-releaselayer. For example, a multilayered tablet can comprise at least oneimmediate release layer comprising an amount of a compound of thepresent invention and at least one controlled release layer whichcomprises an amount of a compound of the present invention. Thecontrolled release layer may provide sustained release of a compound ofthe present invention, for a period of time. Alternatively, theimmediate release layer and the controlled released layer may providesustained release of a compound of the present invention, but atdifferent dosage amounts.

The immediate-release or controlled release dosage forms of the presentinvention can also take the form of pharmaceutical particlesmanufactured by a variety of methods, including but not limited tohigh-pressure homogenization, wet or dry ball milling, or small particleprecipitation. Other methods to make a suitable powder formulation arethe preparation of a solution of active ingredients and excipients,followed by precipitation, filtration, and pulverization, or followed byremoval of the solvent by freeze-drying, followed by pulverization ofthe powder to the desired particle size. These dosage forms can includeimmediate-release particles in combination with controlled-releaseparticles in a ratio sufficient useful for delivering the desireddosages of the compound of the present invention.

In another aspect of the present application, the components arereleased from a multilayered tablet that comprises at least a firstlayer, a second layer and a third layer. Wherein, the layers containingthe compound of the present invention can be optionally separated by oneor more layers of inert materials. In one embodiment the layerscontaining a compound of the present invention have similar rates ofrelease (e.g., all are immediate-release or all are controlled-release).In an alternative embodiment the layers have different rates of release.In this aspect at least one layer is an immediate release layer and atleast one layer is a controlled release layer.

Formulations suitable for parenteral administration include aqueous andnon-aqueous isotonic sterile injection solutions which may containantioxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose sealed containers, for example, ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations suitable for topical administration in the mouth includelozenges comprising the compound of the present invention in a flavoredbase, usually sucrose and acacia or tragacanth; pastilles comprising thecompound of the present invention in an inert base such as gelatin andglycerin, or sucrose and acacia; and mouthwashes comprising the compoundof the present invention in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the compound of the present invention suchcarriers as are known in the art to be appropriate.

Transdermal delivery systems manufactured as an adhesive disc or patchthat slowly releases the active ingredient for percutaneous absorptionmay be used. To this end, permeation enhancers may be used to facilitatetransdermal penetration of the active agent. For example, fortransdermal administration, the compound of the present invention may becombined with skin penetration enhancers, such as propylene glycol,polyethylene glycol, isopropanol, ethanol, oleic acid,N-methylpyrrolidone, dimethyl sulfoxide, and the like, which increasethe permeability of the skin to the compound of the present invention,and permit it to penetrate through the skin and into the bloodstream.The compound of the present invention may also be combined with apolymeric substance, such as ethylcellulose, hydroxypropyl cellulose,ethylene/vinylacetate, polyvinyl pyrrolidone, and the like, to providethe composition in gel form, which may be dissolved in solvent, such asmethylene chloride, evaporated to the desired viscosity, and thenapplied to backing material to provide a patch. The compound of thepresent invention may be administered transdermally to achieve a localconcentration of the active agent or to achieve systemic administrationof the active agent.

Generally speaking, transdermal drug delivery systems are commonlyeither reservoir-type or matrix-type devices. Both types of devicesinclude a backing layer that forms the outer surface of the finishedtransdermal device and which is exposed to the environment during use,and a release liner or protective layer that forms the inner surface andwhich covers the adhesive means for affixing the devices to the skin ormucosa of a user. The release liner or protective layer is removed priorto application, exposing the adhesive means which is typically apressure-sensitive adhesive. The active agent is located between therelease liner and backing layer, usually solubilized or dispersed in asolvent or carrier composition. In some embodiments, the outer surfaceof the transdermal device (e.g., patch) is adapted to associate with asecond component, such as a heating compartment (e.g., electrical orchemical means for providing controlled and consistent increase intemperature).

Compositions of the present invention may be used to prevent, diagnose,monitor and/or treat any suitable disorder, including, but not limitedto, cancer. In some embodiments, the disorder is a gastrointestinalcancer, such as an anal cancer, an esophageal cancer, a stomach cancer,a liver cancer, a gallbladder cancer, a pancreatic cancer, a coloncancer or a rectal cancer. In some embodiments, the disorder is lungcancer. In some embodiments, the disorder is a metastatic disorder(e.g., metastatic cancer).

Compositions of the present invention may target one or more biologicaltargets that are relevant to the prevention and/or treatment of cancer.

Compositions of the present invention may be used in combination with atleast one supplemental agent. In some embodiments, the at least onesupplemental agent comprises a therapeutic agent such as an antitumoralkylating agent, an antitumor antimetabolite, an antitumor antibiotics,a plant-derived antitumor agent, an antitumor organoplatinum compound,an antitumor campthotecin derivative, an antitumor tyrosine kinaseinhibitor, a monoclonal antibody, an interferon, a biological responsemodifier, a hormonal anti-tumor agent, an angiogenesis inhibitor, ananti-metastatic agent, a differentiating agent, a chemotherapeuticagent, a chemopreventative agent, a gene therapy agent, an enzymaticinhibitor or a pharmaceutically acceptable salt or prodrug of any of theforegoing. The composition(s) and the supplemental agent can actadditively or, more preferably, synergistically.

In some embodiments, the composition may be used in combination withsurgery, radiation therapy, chemotherapy, gene therapy, RNA therapy,adjuvant therapy, immunotherapy, nanotherapy or a combination thereof.

Compositions of the present invention may be formulated so as to besuitable for administration via any known method, including, but notlimited to, oral, parenteral (e.g., intraarterial, intravenous (i.v.),subcutaneous, intramuscular and intrathecal), intraperitoneal (i.p.),intrarectal, intravaginal, intranasal, intragastric, intratracheal,sublingual, transcutaneous, intrapulmonary and topical administration.In some embodiments, the composition is formulated for oral, parenteral,topical or rectal administration. In some embodiments, the compositionis formulated for administration via inhalation (e.g., as a spray orpowder). In some embodiments, the composition is formulated for depotadministration.

Compositions of the present invention may be administered intravenouslyor by catheter-based techniques, or a combination thereof, with orwithout associated delivery devices (i.e., pumps). For example, apharmaceutical composition of the present invention can be administeredintravenously, in or associated with cardioplegia solutions, via localdelivery procedures including direct injection into grafts or nativearteries, and via perfusion-assisted techniques.

Compositions of the present application can be infused intravenously,while other therapeutically active agents are delivered to the targetorgan selectively, or both therapies can be delivered by eitherintravenous or intravascular selective administration.

The present invention provides methods of producing and using compoundsof the present invention.

In some embodiments, the present invention provides a method ofproducing a compound of the present invention, said method comprising,consisting essentially of or consisting of conjugating a first moietyand a second moiety, wherein the first moiety is aspirin, an aspirinanalog or an aspirin derivative and the second moiety is stilbene(1,2-diphenylethene), an analog or derivative of stilbene, gingerol(6-gingerol; 5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone), ananalog derivative of ginergol, shogaol (6-shogaol;1-(4-Hydroxy-3-methoxyphenyl)dec-4-en-3-one), an analog or derivative ofshogaol, zingerone (4-(4-hydroxy-3-methoxyphenyl)-2-butanone) or ananalog or derivative of zingerone.

Any suitable aspirin derivative or analog may be used to producecompounds of the present invention, including, but not limited to,

wherein R₅ is —OH or —O—C₁₋₆ alkyl. In some embodiments, R₅ is —OMe,—OEt, —OPr, or —OBu.

Any suitable isomer of stilbene may be used to produce compounds of thepresent invention, including (E)-stilbene and (Z)-stilbene.

Any suitable stilbene derivative or analog may be used to producecompounds of the present invention, including, but not limited to,hydroxylated derivatives of stilbene such as resveratrol, pterostilbene,piceatannol and pinosylvin. In some embodiments, the stilbene derivativeor analog is a derivative or analog of resveratrol (e.g., alkylatedresveratrol derivatives and methylated resveratrol derivatives), aderivative or analog of pterostilbene, a derivative or analog ofpiceatannol or a derivative or analog of pinosylvin. In someembodiments, the stilbene derivative or analog is an alkylatedresveratrol derivative of Formula IX

wherein each of R₁ and R₂ independently is —H or a C₁-C₆ carbon chain.In some embodiments, the stilbene derivative or analog is a compound ofFormula X

wherein each of R₃ and R₄ independently is —H or a C₁-C₆ carbon chain.

The present invention provides methods of 1) preventing, diagnosing,monitoring and/or treating a disorder in a subject in need thereof, 2)reducing one or more adverse effects associated with the treatment of adisorder and/or 3) increasing therapeutic efficacy in the treatment of adisorder.

In some embodiments, the method comprises, consists essentially of orconsists of administering to said subject a therapeutically effectiveamount of a composition of the present invention. In some suchembodiments, the therapeutically effective amount comprises a preventioneffective amount. In some embodiments, the therapeutically effectiveamount comprises a treatment effective amount.

In some embodiments, the method comprises, consists essentially of orconsists of administering to said subject a therapeutically effectiveamount of a compound of Formula I

or a pharmaceutically acceptable salt or prodrug thereof, wherein E is—C—, —O—, —S— or is absent; each of R_(A) and R_(C) is independently —Hor —OH; each of R_(B) and R_(D) is independently —H, —OH or —O—C₁₋₆alkyl; and R_(E) is —OH or —O—C₁₋₆ acyl. In some such embodiments, E is—O—; each of R_(A) and R_(C) is independently —H or —OH; each of R_(D)and R_(B) is independently —H, —OH or —O—C₁₋₆alkyl; and R_(E) is —H, —OHor —O—C₁₋₆ acyl. In some such embodiments, one of R_(B) and R_(D) is —Hand the other is —OH or —O—C₁₋₆ alkyl. In some such embodiments, R_(E)is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some suchembodiments, one of R_(B) and R_(D) is —H and the other is —OH or—O—C₁₋₆alkyl; and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or—O—C(O)-Bu. In some such embodiments, E is —C—; one of R_(B) and R_(D)is —H and the other is —OH or —O—C₁₋₆ alkyl; and R_(E) is —OH,—O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some suchembodiments, E is —O—; one of R_(B) and R_(D) is —H and the other is —OHor —O—C₁₋₆alkyl; and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr,or —O—C(O)-Bu. In some such embodiments, E is absent; one of R_(B) andR_(D) is —H and the other is —OH or —O—C₁₋₆alkyl; and R_(E) is —OH,—O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some suchembodiments, one of R_(B) and R_(D) is —H and the other is —OH, —OMe,—OEt, —OPr, or —OBu. In some such embodiments, R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is —C—; one of R_(B) and R_(D) is —H and the otheris —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is —O—; one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is absent; one of R_(B) and R_(D) is —H and theother is —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments,R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are —OH. In somesuch embodiments, at least two of R_(B), R_(C) and R_(D) are —OH. Insome such embodiments, E is —C— and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O— and at least two ofR_(B), R_(C) and R_(D) are —OH. In some such embodiments, E is absentand at least two of R_(B), R_(C) and R_(D) are —OH. In some suchembodiments, E is —C—; R_(E) is —OH and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O—; R_(E) is —OH and atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments, Eis absent; R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are—OH. In some such embodiments, neither R_(B) nor R_(D) is —OMe. In somesuch embodiments, each of R_(B) and R_(D) is independently —H, —OH. Insome such embodiments, R_(E) is —O—C(O)-Me. In some such embodiments,each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —C—; each of R_(B) and R_(D)is independently —H, —OH, or —OMe; and R_(E) is —O—C(O)-Me. In some suchembodiments, E is —O—; each of R_(B) and R_(D) is independently —H, —OH,or —OMe; and R_(E) is —O—C(O)-Me. In some such embodiments, E is absent;each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —O— and R_(A) is —OH. In somesuch embodiments, E is —O— and R_(A) is —H.

In some embodiments, the method comprises, consists essentially of orconsists of administering to said subject a therapeutically effectiveamount of a compound of Formula IA

or a pharmaceutically acceptable salt or prodrug thereof, wherein E is—C—, —O—, —S— or is absent; each of R_(A) and R_(C) is independently —Hor —OH; each of R_(B) and R_(D) is independently —H, —OH or—O—C₁₋₆alkyl; and R_(E) is —OH or —O—C₁₋₆ acyl. In some suchembodiments, E is —O—; each of R_(A) and R_(C) is independently —H or—OH; each of R_(D) and Re is independently —H, —OH or —O—C₁₋₆alkyl; andR_(E) is —H, —OH or —O—C₁₋₆ acyl. In some such embodiments, one of R_(B)and R_(D) is —H and the other is —OH or —O—C₁₋₆ alkyl. In some suchembodiments, R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or—O—C(Q)-Bu. In some such embodiments, one of R_(B) and R_(D) is —H andthe other is —OH or —O—C₁₋₆alkyl; and R_(E) is —OH, —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is—C—; one of Re and R_(D) is —H and the other is —OH or —O—C₁₋₆ alkyl;and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. Insome such embodiments, E is —O—; one of R_(B) and R_(D) is —H and theother is —OH or —O—C₁₋₆ alkyl; and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is absent; one ofR_(B) and R_(D) is —H and the other is —OH or —O—C₁₋₆ alkyl; and R_(E)is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some suchembodiments, one of R_(B) and R_(D) is —H and the other is —OH, —OMe,—OEt, —OPr, or —OBu. In some such embodiments, R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is —C—; one of R_(B) and R_(D) is —H and the otheris —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is —O—; one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is absent; one of R_(B) and R_(D) is —H and theother is —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments,R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are —OH. In somesuch embodiments, at least two of R_(B), R_(C) and R_(D) are —OH. Insome such embodiments, E is —C— and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O— and at least two ofR_(B), R_(C) and R_(D) are —OH. In some such embodiments, E is absentand at least two of R_(B), R_(C) and R_(D) are —OH. In some suchembodiments, E is —C—; R_(E) is —OH and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O—; R_(E) is —OH and atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments, Eis absent; R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are—OH. In some such embodiments, neither R_(B) nor R_(D) is —OMe. In somesuch embodiments, each of R_(B) and R_(D) is independently —H, —OH. Insome such embodiments, R_(E) is —O—C(O)-Me. In some such embodiments,each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —C—; each of R_(B) and R_(D)is independently —H, —OH, or —OMe; and R_(E) is —O—C(O)-Me. In some suchembodiments, E is —O—; each of R_(B) and R_(D) is independently —H, —OH,or —OMe; and R_(E) is —O—C(O)-Me. In some such embodiments, E is absent;each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —O— and R_(A) is —OH. In somesuch embodiments, E is —O— and R_(A) is —H.

In some embodiments, the method comprises, consists essentially of orconsists of administering to said subject a therapeutically effectiveamount of a compound of Formula IB

or a pharmaceutically acceptable salt or prodrug thereof, wherein E is—C—, —O—, —S— or is absent; each of R_(A) and R_(C) is independently —Hor —OH; each of R_(B) and R_(D) is independently —H, —OH or—O—C₁₋₆alkyl; and R_(E) is —OH or —O—C₁₋₆ acyl. In some suchembodiments, E is —O—; each of R_(A) and R_(C) is independently —H or—OH; each of R_(D) and R_(B) is independently —H, —OH or —O—C₁₋₆alkyl;and R_(E) is —H, —OH or —O—C₁₋₆ acyl. In some such embodiments, one ofR_(B) and R_(D) is —H and the other is —OH or —O—C₁₋₆alkyl. In some suchembodiments, R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or—O—C(O)-Bu. In some such embodiments, one of R_(B) and R_(D) is —H andthe other is —OH or —O—C₁₋₆alkyl; and R_(E) is —OH, —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is—C—; one of R_(B) and R_(D) is —H and the other is —OH or —O—C₁₋₆alkyl;and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. Insome such embodiments, E is —O—; one of R_(B) and R_(D) is —H and theother is —OH or —O—C₁₋₆alkyl; and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is absent; one ofR_(B) and R_(D) is —H and the other is —OH or —O—C₁₋₆alkyl; and R_(E) is—OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some suchembodiments, one of R_(B) and R_(D) is —H and the other is —OH, —OMe,—OEt, —OPr, or —OBu. In some such embodiments, R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is —C—; one of R_(B) and R_(D) is —H and the otheris —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, E is —O—; one ofR_(B) and R_(D) is —H and the other is —OH, —OMe, —OEt, —OPr, or —OBu;and R_(E) is —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In somesuch embodiments, E is absent; one of R_(B) and R_(D) is —H and theother is —OH, —OMe, —OEt, —OPr, or —OBu; and R_(E) is —O—C(O)-Me,—O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments,R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are —OH. In somesuch embodiments, at least two of R_(B), R_(C) and R_(D) are —OH. Insome such embodiments, E is —C— and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O— and at least two ofR_(B), R_(C) and R_(D) are —OH. In some such embodiments, E is absentand at least two of R_(B), R_(C) and R_(D) are —OH. In some suchembodiments, E is —C—; R_(E) is —OH and at least two of R_(B), R_(C) andR_(D) are —OH. In some such embodiments, E is —O—; R_(E) is —OH and atleast two of R_(B), R_(C) and R_(D) are —OH. In some such embodiments, Eis absent; R_(E) is —OH and at least two of R_(B), R_(C) and R_(D) are—OH. In some such embodiments, neither R_(B) nor R_(D) is —OMe. In somesuch embodiments, each of R_(B) and R_(D) is independently —H, —OH. Insome such embodiments, R_(E) is —O—C(O)-Me. In some such embodiments,each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —C—; each of R_(B) and R_(D)is independently —H, —OH, or —OMe; and R_(E) is —O—C(O)-Me. In some suchembodiments, E is —O—; each of R_(B) and R_(D) is independently —H, —OH,or —OMe; and R_(E) is —O—C(O)-Me. In some such embodiments, E is absent;each of R_(B) and R_(D) is independently —H, —OH, or —OMe; and R_(E) is—O—C(O)-Me. In some such embodiments, E is —O— and R_(A) is —OH. In somesuch embodiments, E is —O— and R_(A) is —H.

In some embodiments, the method comprises, consists essentially of orconsists of administering to said subject a therapeutically effectiveamount of a compound of Formula II

or a pharmaceutically acceptable salt or prodrug thereof, wherein eachof R_(B) and R_(D) is independently —OH or —O—C₁₋₆alkyl; and R_(E) is—O—C(O)-Me. In some such embodiments, each of R_(B) and R_(D) isindependently —OH or —O—C₁₋₆alkyl. In some such embodiments, each ofR_(B) and R_(D) is —OH. In some such embodiments, each of R_(B) andR_(D) is —O—C₁₋₆alkyl. In some such embodiments, each of R_(B) and R_(D)is independently —O—C₁₋₃alkyl. In some such embodiments, each of R_(B)and R_(D) is —O—C₁₋₃alkyl. In some such embodiments, each of R_(B) andR_(D) is —O-Me. In some such embodiments, neither R_(B) nor R_(D) is—OMe. In some such embodiments, one of R_(B) and R_(D) is —OH and theother is —O—C₁₋₆ alkyl. In some such embodiments, one of R_(B) and R_(D)is —OH and the other is —OMe, —OEt, —OPr, or —OBu. In some suchembodiment each of R_(B) and R_(D) independently is —OH, —OMe, —OEt,—OPr, or —OBu. In some such embodiments each of R_(B) and R_(D)independently is —OH, —OMe or —OEt.

In some embodiments, the method comprises, consists essentially of orconsists of administering to said subject a therapeutically effectiveamount of a compound of Formula III

or a pharmaceutically acceptable salt or prodrug thereof, wherein R_(A)is —H or —OH; R_(C) is —H, —OH, or —O—C₁₋₆ alkyl; and R_(E) is —OH or—O—C₁₋₆ acyl. In some such embodiments, R_(C) is —H, —OH, —OMe, —OEt,—OPr, or —OBu. In some such embodiments, R_(E) is —OH or O—C₁₋₃ acyl. Insome such embodiments, R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr,or —O—C(O)-Bu. In some such embodiments, each of R_(A) and R_(C) is —OH.In some such embodiments, each of R_(A) and R_(E) is —OH. In some suchembodiments, each of R_(C) and R_(E) is —OH. In some such embodiments,R_(A) is —OH; R_(C) is —H or —OH; and R_(E) is —OH or —O—C₁₋₆ acyl. Insome such embodiments, R_(A) is —OH; R_(C) is —H or —OH; and R_(E) is—OH or O—C₁₋₃ acyl. In some such embodiments, R_(E) is —O—C(O)-Me. Insome such embodiments, R_(C) is —OH and R_(E) is —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, —O—C(O)-Bu. In some such embodiments, R_(C) is —OH and R_(E)is —O—C(O)-Me. In some embodiments, each of R_(A) and R_(C) is —OH andR_(E) is —O—C(O)Me. In some such embodiments, R_(A) is —OH; R_(C) is —H,—OH, —OMe, —OEt, —OPr, or —OBu and R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et,—O—C(O)—Pr, or —O—C(O)-Bu. In some such embodiments, R_(A) is —H; R_(C)is —OH, or —O—C₁₋₆ alkyl; and R_(E) is —OH or —O—C₁₋₆ acyl. In some suchembodiments, R_(A) is —H; R_(C) is —OH, —OMe, —OEt, —OPr, or —OBu; andR_(E) is —OH or —O—C₁₋₆ acyl.

In some embodiments, the method comprises, consists essentially of orconsists of administering to said subject a therapeutically effectiveamount of a compound of Formula IV

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the method comprises, consists essentially of orconsists of administering to said subject a therapeutically effectiveamount of a compound of Formula V

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the method comprises, consists essentially of orconsists of administering to said subject a therapeutically effectiveamount of a compound of Formula VI

or a pharmaceutically acceptable salt or prodrug thereof, wherein R_(E)is —H, —OH, or —O—C₁₋₆ acyl; R_(F) is optionally substituted C₁₋₁₂ alkylor optionally substituted C₁₋₁₂ alkenyl; and R_(G) is —H or C₁₋₆alkyl.In some such embodiments, R_(E) is —O—C(O)—C₁₋₃alkyl. In some suchembodiments, R_(E) is —OH, —O—C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or—O—C(O)-Bu. In some such embodiments, R_(G) is —H or —Me. In some suchembodiments, R_(E) is —O—C(O)-Me and R_(G) is —Me. In some suchembodiments, R_(F) is optionally substituted C₁₋₉alkyl or optionallysubstituted C₁₋₉ alkenyl. In some such embodiments, R_(F) is optionallysubstituted C₁₋₇alkyl or optionally substituted C₁₋₇alkenyl. In somesuch embodiments, R_(F) is

wherein n=3, 5, or 7. In some such embodiments, R_(F) is optionallysubstituted C₂₋₇alkyl or optionally substituted C₂₋₇alkenyl. In somesuch embodiments, R_(F) is optionally substituted C₂₋₉ alkyl oroptionally substituted C₂₋₉ alkenyl. In some such embodiments, R_(F) isoptionally substituted C₂₋₁₁alkyl or optionally substituted C₂₋₁₁alkenyl. In some embodiments R_(G) is —Me; R_(E) is —OH or —O—C(O)-Me;and R_(F) is optionally substituted C₂₋₇ alkyl or optionally substitutedC₂₋₇alkenyl. In some such embodiments, R_(G) is —H or —Me; R_(E) is —OH,-Q-C(O)-Me, —O—C(O)-Et, —O—C(O)—Pr, or —O—C(O)-Bu; and R_(F) is:

wherein n=3, 5, or 7; in some variations, n=3; in some variations n=5;in some variations n=7.

In some embodiments, the method comprises, consists essentially of orconsists of administering to said subject a therapeutically effectiveamount of a compound of Formula VII

or a pharmaceutically acceptable salt or prodrug thereof, wherein R_(F)is optionally substituted C₁₋₁₂ alkyl or optionally substituted C₁₋₁₂alkenyl. In some such embodiments, R_(F) is optionally substituted C₁₋₉alkyl or optionally substituted C₁₋₉ alkenyl. In some such embodiments,R_(F) is optionally substituted C₁₋₇ alkyl or optionally substitutedC₁₋₇ alkenyl. In some such embodiments, R_(F) is optionally substitutedC₂₋₇alkyl or optionally substituted C₂₋₇ alkenyl. In some suchembodiments, R_(F) is optionally substituted C₂₋₉ alkyl or optionallysubstituted C₂₋₉alkenyl. In some such embodiments, R_(F) is optionallysubstituted C₂₋₁₁ alkyl or optionally substituted C₂₋₁₁ alkenyl. In someembodiments, R_(F) is optionally substituted C₇ alkyl or optionallysubstituted C₇ alkenyl. In some such embodiments, R_(F) is optionallysubstituted C₉ alkyl or optionally substituted C₉ alkenyl. In some suchembodiments, R_(F) is optionally substituted C₁₁ alkyl or optionallysubstituted C₁₁ alkenyl. In some such embodiments, R_(F) is

wherein n=3, 5, or 7; in some variations, n=3; in some variations n=5;in some variations n=7.

In some embodiments, the method comprises, consists essentially of orconsists of administering to said subject a therapeutically effectiveamount of a pharmaceutical composition of the present invention.

In some embodiments, the method comprises, consists essentially of orconsists of administering to said subject a therapeutically effectiveamount of a compound comprising a first moiety and a second moiety,wherein the first and second moieties are covalently linked, wherein thefirst moiety is aspirin, an aspirin analog or an aspirin derivative andwherein the second moiety is stilbene, an analog or derivative ofstilbene, gingerol, an analog or derivative of gingerol, shogaol, ananalog or derivative of shogaol, zingerone or an analog or derivative ofzingerone.

In some such embodiments, the composition is a compound of the presentinvention. In some such embodiments, the composition is a pharmaceuticalcomposition of the present invention. In some such embodiments, thecomposition is a compound comprising a first moiety and a second moiety,wherein the first and second moieties are covalently linked, wherein thefirst moiety is aspirin, an aspirin analog or an aspirin derivative andwherein the second moiety is stilbene, an analog or derivative ofstilbene, gingerol, an analog or derivative of gingerol, shogaol, ananalog or derivative of shogaol, zingerone or an analog or derivative ofzingerone.

In some embodiments, administration of the composition results in theprevention and/or treatment of a first disorder and the preventionand/or treatment of a second disorder. For example, administration ofthe composition may result in the treatment of rectal cancer and theprevention of colon cancer (by preventing metastasis, for example).

In some embodiments, the subject exhibits one or more risk factorsassociated with the disorder. For example, the subject may have afamilial history of cancer, one or more pre-cancerous lesions,premalignant cells, preneoplastic cells or other aberrant phenotypesindicating probably progression to a cancerous state.

In some embodiments, the subject is a human.

In some embodiments, the composition is administered in combination withsurgery, radiation therapy, chemotherapy, gene therapy, RNA therapy,adjuvant therapy, immunotherapy, nanotherapy or a combination thereof.

In some embodiments, the method further comprises administering to thesubject at least one supplemental agent. In some embodiments, the atleast one supplemental agent comprises a therapeutic agent such as anantitumor alkylating agent, an antitumor antimetabolite, an antitumorantibiotics, a plant-derived antitumor agent, an antitumororganoplatinum compound, an antitumor campthotecin derivative, anantitumor tyrosine kinase inhibitor, a monoclonal antibody, aninterferon, a biological response modifier, a hormonal anti-tumor agent,an angiogenesis inhibitor, an anti-metastatic agent, a differentiatingagent, a chemotherapeutic agent, a chemopreventative agent, a genetherapy agent, an enzymatic inhibitor or a pharmaceutically acceptablesalt or prodrug of any of the foregoing. In some such embodiments, theother therapeutic agent is administered prior to, concomitant with orsubsequent to administering the composition of the present invention. Insome such embodiments, the composition(s) of the present invention andthe supplemental agent can act additively or, more preferably,synergistically.

Combination therapy may include the administration of a composition ofthe present invention and at least one supplemental agent as part of aspecific treatment regimen intended to provide the beneficial effectfrom the co-action of the therapeutic agents. The beneficial effects ofthe combination may include, but are not limited to, pharmacokineticand/or pharmacodynamic co-action resulting from the combination oftherapeutic agents. Administration of the therapeutic agents incombination may be carried out over a defined time period (e.g.,minutes, hours, days or weeks, depending upon the combination selected).Combination therapy can be carried out either sequentially orsubstantially simultaneously. In the case of sequential administrationof more than one therapeutic agent, each therapeutic agent isadministered at a different time. In the case of simultaneousadministration, at least two of the therapeutic agents are administeredin a substantially simultaneous manner, either in the samepharmaceutical composition or in different pharmaceutical compositions.Substantially simultaneous administration can be accomplished, forexample, by administering to the subject a single capsule having a fixedratio of each therapeutic agent or in multiple, single capsules for eachof the therapeutic agents. In one embodiment, a composition comprising aconjugate of the application is administered concurrently with theadministration of another therapeutic agent, which can be part of thesame composition as the conjugate of the application or a differentcomposition. In another embodiment, a composition comprising a conjugateof the application is administered prior to, or subsequent to,administration of another therapeutic agent.

Sequential or substantially simultaneous administration of eachtherapeutic agent can be effected by any appropriate route including,but not limited to, oral routes, intravenous routes, intramuscularroutes, and direct absorption through mucous membrane tissues. Thetherapeutic agents can be administered by the same route or by differentroutes. For example, a first therapeutic agent of the combinationselected can be administered by intravenous injection while the othertherapeutic agents of the combination can be administered orally.Alternatively, for example, all therapeutic agents can be administeredorally or all therapeutic agents can be administered by intravenousinjection. The sequence in which the therapeutic agents are administeredis not narrowly critical. In some embodiments, the therapeutic agentsare administered within about 1 minute, 5 minutes, 10 minutes, 15minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 50 minutes, 1hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5hours, 5 hours, 5.5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours,11 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1week, 2 weeks, 3 weeks or 4 weeks of one another.

Combination therapy also encompasses the administration of the conjugateas described above in further combination with other therapies includingbut not limited to chemotherapy, surgery, radiation therapy, genetherapy, immunotherapy, RNA therapy, adjuvant therapy, nanotherapy or acombination thereof. Where the combination therapy further comprises anon-drug treatment, the non-drug treatment can be conducted at anysuitable time so long as a beneficial effect from the co-action of thecombination of the therapeutic agents and non-drug treatment isachieved. For example, in appropriate cases, the beneficial effect isstill achieved when the non-drug treatment is temporally removed fromthe administration of the therapeutic agents, by a significant period oftime. The conjugate and the other pharmacologically active agent can beadministered to a subject simultaneously, sequentially or incombination. It will be appreciated that when using a combination of theapplication, the conjugate of the application and the otherpharmacologically active agent can be in the same pharmaceuticallyacceptable carrier and therefore administered simultaneously. They canbe in separate pharmaceutical carriers such as conventional oral dosageforms which are taken simultaneously. The term “combination” furtherrefers to the case where the compounds are provided in separate dosageforms and are administered sequentially.

The composition may be administered using any suitable method known inthe art, including, but not limited to, oral, parenteral (e.g.,intraarterial, intravenous (i.v.), subcutaneous, intramuscular andintrathecal), intraperitoneal (i.p.), intrarectal, intravaginal,intranasal, intragastric, intratracheal, sublingual, transcutaneous,intrapulmonary and topical administration. In some embodiments, thecompound or pharmaceutical composition is administered orally,parenterally, topically or rectally. In some embodiments, the compoundor pharmaceutical composition is administered via inhalation (e.g., as aspray or powder). In some embodiments, the compound or pharmaceuticalcomposition is injected directly into a tumor. In some embodiments, thecompound or pharmaceutical composition is administered as a depotformulation. In some embodiments, the compound or pharmaceuticalcomposition is administered intraarterially and/or intravenously via acatheter.

Methods of the present invention may be used to prevent, diagnose,monitory and/or treat any suitable disorder, including, but not limitedto, cancer. In some embodiments, the disorder is a gastrointestinalcancer, such as an anal cancer, an esophageal cancer, a stomach cancer,a liver cancer, a gallbladder cancer, a pancreatic cancer, a coloncancer or a rectal cancer. In some embodiments, the disorder is lungcancer. In some embodiments, the disorder is a metastatic disorder(e.g., metastatic cancer).

In some embodiments, administration of the composition produces fewerand/or less pronounced adverse effects (e.g., adverse GI effectsassociated with the administration of aspirin) than the individualmoieties that make up the compound. For example, administration of aconjugate compound comprising an aspirin derivative and a stilbenederivative may produce fewer adverse effects than administration of theaspirin derivative and the stilbene derivative (and/or administration ofaspirin and stilbene themselves). Administration of a sustained-releaseformulation of the composition may further reduce any adverse effects,allowing for the administration of higher dosages of the composition.

In some embodiments, administration of the composition produces greaterand/or more prolonged therapeutic effects than the individual moietiesthat make up the compound. For example, administration of a conjugatecompound comprising aspirin and gingerol may have a more pronouncedanti-tumorigenesis effect than administration of aspirin and gingerol(and/or administration of an aspirin derivative/analog and a gingerolderivative/analog). Accordingly, methods of the present invention mayachieve adequate levels of anti-tumor efficacy at a lower dosage thanwould be required for administration of the individual moieties thatmake up the compound.

It will be understood that the specific dosage level for any particularsubject will depend on a variety of factors including, but not limitedto, the activity of the composition being administered; the age, bodyweight, general health, sex and diet of the subject; the time and routeof administration; the rate of excretion; and other drugs which havepreviously been administered.

Convenient dosing includes, but is not limited to, a once a day or twicea day administration, such as a tablet or capsule, as well asintravenous infusions. The use of time-release preparations to controlthe rate of release of the compound of the present invention as well ascontinuous infusions may also be employed. The dose may be administeredin as many divided doses as is convenient.

Unit dosage formulations can be those containing a daily dose or unit,daily sub-dose, or an appropriate fraction thereof, of a composition ofthe present invention. The unit dose may be for oral consumption, suchas by a tablet or capsule, or for infusion, or administered by othermeans as disclosed herein. In some embodiments, the dose amount isprovided once a day, twice a day, 3 times a day, or 4 or more times aday. In other embodiments, the dose amount is provided twice a week,once a week, twice a month or once a month. For example, a dose can beprovided twice a day, 3 times a day, or 4 or more times a day. In someembodiments, such a dose is provided twice a week, once a week, twice amonth or once a month. The amount may be provided by oral consumption,infusion, or administered by other means familiar to those of skill inthe art, such as transdermal or transmucosal.

In some embodiments, the unit dose may be provided as an infusion. Forexample, the compositions described herein can be administeredintravenously, such as by an IV drip using IV solutions well known inthe art (e.g., isotonic saline (0.9% NaCl) or dextrose solution (e.g.,5% dextrose), optionally the intravenous solution further includespreservatives, e.g. Sodium metabisulfite. For example, a dose can beprovided by infusion, such as by IV drip once a day, twice a week, oncea week, twice a month or once a month. Alternately, the unit dose isinfused once a day, twice a day, 3 times a day, or 4 or more times aday, for a period of time.

In some embodiments, the unit dose is from about 0.5 to about 500 mg/kg,about 0.5 to about 450 mg/kg, about 0.5 to about 400 mg/kg, about 0.5 toabout 350 mg/kg, about 0.5 to about 300 mg/kg, about 0.5 to about 250mg/kg, about 0.5 to about 200 mg/kg, about 0.5 to about 150 mg/kg, about0.5 to about 100 mg/kg, about 0.5 to about 50 mg/kg, about 0.5 to about25 mg/kg, about 0.5 to about 20 mg/kg, about 0.5 to about 15 mg/kg,about 0.5 to about 10 mg/kg, about 0.5 to about 5 mg/kg; about 1 toabout 500 mg/kg, about 1 to about 450 mg/kg, about 1 to about 400 mg/kg,about 1 to about 350 mg/kg, about 1 to about 300 mg/kg, about 1 to about250 mg/kg, about 1 to about 200 mg/kg, about 1 to about 150 mg/kg, about1 to about 100 mg/kg, about 1 to about 50 mg/kg, about 1 to about 25mg/kg, about 1 to about 20 mg/kg, about 1 to about 15 mg/kg, about 1 toabout 10 mg/kg, about 1 to about 5 mg/kg, about 2 to about 500 mg/kg,about 2 to about 450 mg/kg, about 2 to about 400 mg/kg, about 2 to about350 mg/kg, about 2 to about 300 mg/kg, about 2 to about 250 mg/kg, about2 to about 200 mg/kg, about 2 to about 150 mg/kg, about 2 to about 100mg/kg, about 2 to about 50 mg/kg, about 2 to about 25 mg/kg, about 2 toabout 20 mg/kg, about 2 to about 15 mg/kg, about 2 to about 10 mg/kg,about 2 to about 5 mg/kg, 3 to about 500 mg/kg, about 3 to about 450mg/kg, about 3 to about 400 mg/kg, about 3 to about 350 mg/kg, about 3to about 300 mg/kg, about 3 to about 250 mg/kg, about 3 to about 200mg/kg, about 3 to about 150 mg/kg, about 3 to about 100 mg/kg, about 3to about 50 mg/kg, about 3 to about 25 mg/kg, about 3 to about 20 mg/kg,about 3 to about 15 mg/kg, about 3 to about 10 mg/kg, or about 3 toabout 5 mg/kg of a composition of the present invention (e.g., acompound of the present invention).

In some embodiments, the unit dose is at least about 2 μg/kg, 5 μg/kg,10 μg/kg, 15 μg/kg, 20 μg/kg, 30 μg/kg, 40 μg/kg, 50 μg/kg, 60 μg/kg, 70μg/kg, 80 μg/kg, 90 μg/kg, 100 μg/kg, 150 μg/kg, 200 μg/kg, 250 μg/kg,300 μg/kg, 350 μg/kg, 400 μg/kg, 450 μg/kg, 500 μg/kg, 550 μg/kg, 600μg/kg, 650 μg/kg, 700 μg/kg, 750 μg/kg, 800 μg/kg, 850 μg/kg, 900 μg/kg,950 μg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95mg/kg, 100 mg/kg, 110 mg/kg, 120 mg/kg, 130 mg/kg, 140 mg/kg, 150 mg/kg,160 mg/kg, 170 mg/kg, 180 mg/kg, 190 mg/kg, 200 mg/kg, 250 mg/kg, 300mg/kg, 350 mg/kg. 400 mg/kg, 450 mg/kg, 500 mg/kg or more of acomposition of the present invention (e.g., a compound of the presentinvention).

In some embodiments, the present invention provides a kit comprising,consisting essentially of or consisting of a compound or pharmaceuticalcomposition of the present invention and instructions for using thecompound or pharmaceutical composition to prevent, monitor and/or treata disorder.

In some embodiments, the present invention provides a kit comprising,consisting essentially of or consisting of a composition of the presentinvention, a supplemental composition and instructions for using thecomposition of the present invention and the supplemental composition toprevent, monitor and/or treat a disorder.

Kits of the present invention may comprise instructions for preventing,monitoring and/or treating any suitable disorder, including, but notlimited to, cancer. In some embodiments, the disorder is agastrointestinal cancer, such as an anal cancer, an esophageal cancer, astomach cancer, a liver cancer, a gallbladder cancer, a pancreaticcancer, a colon cancer or a rectal cancer. In some embodiments, thedisorder is lung cancer.

Kits of the present invention may comprise instructions for preventing,monitoring and/or treating a disorder in any suitable subject,including, but not limited to, human subjects.

Kits of the present invention may comprise instructions for preventing,monitoring and/or treating a disorder according to a method of thepresent invention.

Kits of the present invention may comprise any suitable supplementalcompound or composition, including, but not limited to, therapeuticcompounds/compositions. In some embodiments, the supplemental compoundor composition comprises an antitumor alkylating agent, an antitumorantimetabolite, an antitumor antibiotics, a plant-derived antitumoragent, an antitumor organoplatinum compound, an antitumor campthotecinderivative, an antitumor tyrosine kinase inhibitor, a monoclonalantibody, an interferon, a biological response modifier, a hormonalanti-tumor agent, an angiogenesis inhibitor, a differentiating agent ora pharmaceutically acceptable salt or prodrug of any of the foregoing.In some embodiments, the supplemental compound or composition comprisesan active agent that reduces one or more adverse effects associated withadministration of the compound or pharmaceutical composition of thepresent invention. In some embodiments, the supplemental compound orcomposition comprises an active agent that enhances the efficacy of thecompound or pharmaceutical composition of the present invention.

EXAMPLES

The following examples are for illustrative purposes only and are notintended to be a detailed catalogue of all the different ways in whichthe present invention may be implemented or of all the features that maybe added to the present invention.

Starting materials useful for preparing compounds of the presentinvention and intermediates thereof are commercially available and/orcan be prepared by well-known synthetic methods. Other methods forsynthesis of the compounds described herein are either described in theart or will be readily apparent to the skilled artisan in view of thereferences provided above and can be used to synthesize conjugates ofthe application. One skilled in the art will therefore appreciate thatthe following Examples are exemplary and that numerous changes,modifications, and alterations can be employed without departing fromthe scope of the presently disclosed subject matter.

Example 1 Synthesis of Aspirin-Stilbene Derivative Compounds

As shown in Scheme I below, stilbene derivatives can be reacted withacetylsalicyloyl chloride under basic conditions to yield conjugatecompounds.

Di-methylated resveratrol (pterostilbene; Pt) was reacted with 1.2equivalents of acetylsalicyloyl chloride under basic conditions togenerate pterostilbene aspirinate (PAS; yield: 96%). The structure ofPAS was determined by ¹H, ¹³C, and 2D (HMQC and HMBC) NMR and MSanalysis.

PAS: white solid; ¹H NMR (700 MHz, CDCl₃) δ 6.66 (2H, t, J=2.0 Hz,H-2/6), 6.39 (1H, t, J=2.0 Hz, H-4), 6.99 (1H, d, J=16.1 Hz, H-7), 7.07(1H, d, J=16.1 Hz, H-8), 7.53 (2H, d, J=8.4 Hz, H-10/14), 7.16 (2H, d,J=8.4 Hz, H-11/13), 7.17 (1H, d, J=8.0 Hz, H-4′), 7.62 (1H, dt, J=8.0,1.4 Hz, H-5′), 7.37 (1H, t, J=8.0 Hz, H-6′), 8.21 (1H, dd, J=8.0, 1.4Hz, H-7′), 2.30 (3H, s, CH ₃C═O), and 3.81 (6H, s, OMe-3/5); ¹³C NMR(175 MHz, CDCl₃) δ 139.2 (s, C-1), 104.6 (d, C-2/6), 161.0 (s, C-3/5),100.1 (d, C-4), 129.1 (d, C-7), 128.1 (d, C-8), 135.3 (s, C-9), 127.7(d, C-10/14), 121.9 (d, C-11/13), 150.0 (s, C-12), 163.0 (s, C-1′),122.5 (s, C-2′), 151.2 (s, C-3′), 124.1 (d, C-4′), 134.7 (d, C-5′),126.3 (d, C-6′), 132.3 (d, C-7′), 169.8 (s, CH₃ C═O), 21.1 (q, CH₃C═O),and 55.4 (q, OMe-3/5); positive APCIMS, m/z 419 [M+H]⁺.

Mono-methylated resveratrol (MRes) was reacted with 1.2 equivalents ofacetylsalicyloyl chloride under basic conditions to generatemono-methylated resveratrol aspirinate (MRAS; yield: 80%). The structureof MRAS was determined by ¹HNMR and MS analysis.

MRAS: white solid; ¹H NMR (600 MHz, CDCl₃) δ 6.59 (1H, s, H-2), 6.34(1H, t, J=2.1 Hz, H-4), 6.64 (1H, s, s, H-6), 7.06 (1H, d, J=16.3 Hz,H-7), 6.96 (1H, d, J=16.3 Hz, H-8), 7.53 (2H, d, J=8.6 Hz, H-10/14),7.17 (2H, d, J=8.6 Hz, H-11/13), 7.19 (1H, d, J=8.0 Hz, H-4′), 7.65 (11,dt, J=8.0, 1.6 Hz, H-5′), 7.40 (1H, t, J=8.0 Hz, H-6′), 8.23 (1H, dd,J=8.0, 1.6 Hz, H-7′), 2.32 (3H, s, CH ₃C═O), and 3.82 (3H, s, OMe-3);positive APCIMS, m/z 405 [M+H]⁺.

Resveratrol (Res) was reacted with 1.2 equivalents of acetylsalicyloylchloride under basic conditions to generate two resveratrol aspirinateisomers: RAS (yield: 65%) and RAS-1 (yield: 28%). The compoundstructures were determined by ¹H NMR and MS analysis.

RAS: white solid; ¹H NMR (600 MHz, CD₃OD) δ 6.89 (1H, s, H-2), 6.51 (1H,t, J=2.0 Hz, H-4), 6.84 (1H, s, H-6), 7.09 (1H, d, J=16.3 Hz, H-7), 6.93(1H, d, J=16.3 Hz, H-8), 7.41 (2H, d, J=8.6 Hz, H-10/14), 6.79 (211, d,J=8.6 Hz, H-11/13), 7.26 (1H, d, J=8.0 Hz, H-4′), 7.74 (1H, dt, J=8.0,1.6 Hz, H-5′), 7.47 (1H, t, J=8.0 Hz, H-6′), 8.20 (1H, dd, J=8.0, 1.6Hz, H-7′), and 2.30 (3H, s, CH ₃C═O); ¹³C NMR (125 MHz, CD₃OD); positiveAPCIMS, m/z 391 [M+H]⁺.

RAS-1: white solid; ¹H NMR (600 MHz, CD₃OD) δ 6.53 (2H, d, J=2.0 Hz,H-2/6), 6.24 (1H, t, J=2.0 Hz, H-4), 7.09 (1H, d, J=16.3 Hz, H-7), 7.03(1H, d, J=16.3 Hz, H-8), 7.61 (2H, d, J=8.6 Hz, H-10/14), 7.18 (2H, d,J=8.6 Hz, H-11/13), 7.26 (1H, d, J=8.0 Hz, H-4′), 7.73 (1H, dt, J=8.0,1.6 Hz, H-5′), 7.47 (1H, t, J=8.0 Hz, 11-6′), 8.21 (1H, dd, J=8.0, 1.6Hz, H-7′), and 2.29 (3H, s, CH ₃C═O); positive APCIMS, m/z 391 [M+H]⁺.

Example 2 Synthesis of Aspirin-Shogaol Compounds

As shown in Scheme II below, shogaol and shogaol derivatives can bereacted with acetylsalicyloyl chloride under basic conditions to yield aconjugate compound.

6-Shogaol was reacted with 2.0 equivalents of acetylsalicyloyl chlorideunder basic conditions to generate 6-shogaol aspirinate (SAS; yield:93%). Its structure was determined by ¹HNMR and MS analysis.

SAS: yellow oil; ¹H NMR (600 MHz, CDCl₃) δ 6.85 (1H, d, J=1.7 Hz, H-2),7.02 (1H, d, J=8.0 Hz, H-5), 6.80 (1H, dd, J=8.0, 1.7 Hz, H-6), 2.94(2H, t, J=7.2 Hz, H-1′), 2.88 (2H, t, J=7.2 Hz, 11-2′), 6.11 (1H, d,J=17.0 Hz, H-4′), 6.84 (1H, dt, J=17.0, 7.0 Hz, H-5′), 2.21 (2H, m,H-6′), 1.47 (2H, m, H-7′), 1.35-1.25 (4H, m, H-8′/9′), 0.90 (3H, t,J=6.8 Hz, H-10′), 7.16 (1H, d, J=8.0 Hz, H-4′), 7.62 (1H, dt, J=8.0, 1.6Hz, H-5′), 7.37 (1H, t, J=8.0 Hz, H-6′), 8.23 (1H, dd, J=8.0, 1.6 Hz,H-7′), 2.29 (3H, s, CH ₃C═O), and 3.80 (3H, s, OMe-3); positive APCIMS,m/z 439 [M+H]⁺.

Aspirin-shogaol derivative compounds are formed by substituting6-shogaol with 8-shogaol or 10-shogaol in Scheme II. The structures ofthe resulting conjugate compounds are determined by ¹HNMR and MSanalysis.

Example 3 Synthesis of Aspirin-Gingerol Compounds

As shown in Scheme III below, gingerol and gingerol derivatives can bereacted with acetylsalicyloyl chloride under basic conditions to yield aconjugate compound.

6-Gingerol was reacted with 2.0 equivalents acetylsalicyloyl chlorideunder basic conditions to generate 6-gingerol aspirinate (GAS; yield:99%). Its structure was determined by ¹HNMR and MS analysis.

GAS: yellow oil; ¹H NMR (600 MHz, CDCl₃) δ 6.82 (1H, d, J=1.7 Hz, H-3),6.78 (1H, dd, J=8.0, 1.7 Hz, H-5), 7.02 (1H, d, J 8.0 Hz, H-6), 2.91(2H, t, J=7.2 Hz, H-1′), 2.78 (2H, t, J=7.2 Hz, H-2′), 2.59 (1H, dd,J=17.3, 2.8 Hz, H-4′a), 2.51 (1H, dd, J=17.3, 9.1 Hz, H-4′b), 4.04 (1H,m, H-5′), 1.50-1.47 (2H, m, H-6′), 1.43-1.39 (2H, m, H-7′), 1.35-1.25(4H, m, H-8′/9′), 0.89 (3H, t, J=7.0 Hz, H-10′), 7.16 (1H, d, J=8.0 Hz,H-3″), 7.62 (1H, dt, J=8.0, 1.6 Hz, H-4″), 7.37 (1H, t, J=8.0 Hz, H-5″),8.23 (1H, dd, J=8.0, 1.6 Hz, H-6″), 2.29 (3H, s, H-8″), and 3.80 (3H, s,OMe-2); positive APCIMS, m/z 457 [M+H]⁺.

Aspirin-gingerol derivative compounds are formed by substituting6-gingerol with 8-gingerol or 10-gingerol in Scheme III. The structuresof the resulting conjugate compounds are determined by ¹HNMR and MSanalysis.

Example 4 Synthesis of(E)-(4-(3,5-dihydroxystyryl)phenyl)(2-hydroxyphenyl)methanone

Bromostilene is produced by a Wittig reaction of3,5-dimethoxybenzaldehyde with (4-bromobenzyl)-triphenylphosphoniumbromide. Bromine-lithium exchange of bromide with n-butyllithium,followed by treatment of salicylic aldehyde gives the benzylic alcohol.Oxidation by copper of the benzylic alcohol gives the ketone. Finally,demethylation of the ketone generates product(E)-(4-(3,5-dihydroxystyryl)phenyl)(2-hydroxyphenyl)methanone (FormulaIV; 131). Its structure is determined by ¹HNMR and MS analysis.

Example 5 Synthesis of(E)-2-(4-(3,5-dihydroxystyryl)phenyl)-1-(2-hydroxyphenyl)ethanone

Reductive coupling of 1-bromo-4-(bromomethyl)benzene withO-acetylsalicyloyl chloride produces a ketone, which is treated by borontribromide to form the deacetylated product. A Heck reaction of thedeacetylated product with 1,3-dimethoxy-5-vinylbenzene yields theortho-hydroxy ketone. Demethylation of the ortho-hydroxy ketone givesthe desired product(E)-2-(4-(3,5-dihydroxystyryl)phenyl)-1-(2-hydroxyphenyl)ethanone(Formula V; 152). Its structure is determined by ¹H NMR and MS analysis.

Example 6 Effect of Aspirin-Stilbene Derivative Compounds on ColonCancer Cell Lines

The effects of the aspirin-stilbene derivative conjugates compared tostandards were evaluated based on the inhibition of growth of HCT-116and HT-29 human colon cancer cells. Cells were plated in 96-well platesin growth medium with 10% FBS. After 24 h, the medium was replaced withfresh medium containing test agent with desired final concentration (20,30, 40, 50, and 60 M), and the cells were incubated for 48 h. Viablecells were analyzed using the MTT assay, and the results are shown(FIG. 1) relative to control. Each value represents the mean±S.D. (n=8).FIG. 1, Panel A summarizes the results for aspirin (As), Res, RAS,RAS-1, and the combination of resveratrol and aspirin (Res+As). RAS hada stronger growth inhibitory effect than resveratrol and aspirin alone,and stronger than the combination of resveratrol and aspirin (1:1) onboth HCT-116 and HT-29 human colon cancer cells. FIG. 1, Panel Bsummarizes the results for As, MRes, MRAS and the combination of MResand aspirin (MRes+As). MRAS had weaker growth inhibitory effects thanMRes and the combination of MRes and aspirin (1:1). FIG. 1, Panel Csummarizes the results for As, Pt, PAS, and the combination ofpterostilbene and aspirin (Pt+As). PAS had weaker growth inhibitoryeffects than pterostilbene and the combination of pterostilbene andaspirin (1:1). In addition, RAS had much stronger growth inhibitoryeffects than RAS-1, MRAS, and PAS.

Example 7 Effect of Aspirin-Shogaol Compounds on Colon Cancer Cell Lines

The effects of As, 6-shogaol (6-s), SAS and the combination of 6-shogaoland aspirin (6-s+As) on the growth of HCT-116 and HT-29 human coloncancer cells and H1299 human lung cancer cells were measured. Cells wereplated in 96-well plates in growth medium with 10% FBS. After 24 h, themedium was replaced with fresh medium containing test agent with desiredfinal concentration (5, 7.5, 10, 15, and 20 μM), and the cells wereincubated for 48 h. Viable cells were analyzed using the MTT assay, andthe results are shown relative to control (FIG. 2).

SAS had a stronger growth inhibitory effect than aspirin alone, but lesseffective than 6-shogaol alone and the combination of 6-shogaol andaspirin (1:1) on all cell lines (HCT-116, HT-29, and H-1299) (FIG. 2;each value represents the mean±standard deviation (n=8)).

Example 8 Effect of Aspirin-Gingerol Compounds on Colon Cancer CellLines

The effects of As, 6-gingerol (6g), GAS, and the combination of6-gingerol and aspirin (6g+As) on the growth of HCT-116 and HT-29 humancolon cancer cells and H1299 human lung cancer cells were measured.Cells were plated in 96-well plates in growth medium with 10% FBS. After24 h, the medium was replaced with fresh medium containing test agentwith desired final concentration (20, 40, 60, 80, and 100 μM), and thecells were incubated for 48 h. Viable cells were analyzed using the MTTassay, and the results are shown relative to control (FIG. 3).

GAS had a much stronger growth inhibitory effect than 6-gingerol andaspirin alone, as well as the combination of 6-gingerol and aspirin(1:1) on all cell lines (HCT-116, HT-29, and H-1299) (FIG. 3; each valuerepresents the mean±standard deviation (n=8).

Example 9 Effect of Aspirin-Resveratrol Compounds on Colon Cancer CellLines

The effects of the combination of aspirin and resveratrol (A/R), RAS,RAS-1, 131 and 152 on colony formation of HCT-116 and HT-29 colon cancercells were measured. HCT-116 (100 cells/well) and HT-29 (100 cells/well)cells were seeded in six-well plates. After 24 h, cells were treatedwith various concentrations (20, 40, and 60 μM) of the test compound.After 14 days of culture, media were removed and colonies were washedwith PBS. Colonies were then stained with 0.5% crystal violet for 30min. After thorough rinsing with PBS, the colonies were counted andrecorded. FIG. 4 shows the anti-cell proliferation effect of the testagents using a colony formation assay.

Example 10 Urinary Metabolic Profile of PAS and RAS in Mice

The metabolic profile of Pt using LC/MS 23 was investigated. PAS wasadministered to mice (n=5) by oral gavage (200 mg/kg), and urine sampleswere collected in metabolism cages for 24 h after administration ofvehicle (control mice) or PAS. LC/MS methods were developed to analyzePAS, pterostilbene, and aspirin. LC chromatograms of urine samplescollected from PAS-treated mice obtained using positive APCI-MSinterface (FIG. 5): (A) before and (B) after enzymatic hydrolysis(treated with β-glucuronidase and sulfatase); using negative ESI-MSinterface: (C) before and (D) after enzymatic hydrolysis.

As shown in FIG. 5, Peak 1: salicylic acid; peak 2: salicylic acidglucuronide; peak 3: pterostilbene; peak 4: pterostilbene glucuronide;peak 5: pterostilbene sulfate; peak 6: mono-demethylated pterostilbene;peak 7: mono-demethylated pterostilbene glucuronide; peak 8:mono-demethylated pterostilbene sulfate; peak 9: mono-hydroxylatedpterostilbene; and peak 10: mono-hydroxylated pterostilbene glucuronide.

PAS had the highest response under positive APCI/MS mode, and aspirinand salicylic acid had the highest response under negative ESI/MS mode.Both positive APCI/MS and negative ESI/MS modes are sensitive topterostilbene. However, aspirin and salicylic acid are hardly detectableunder positive APCI/MS mode, and PAS is not detectable under negativeESI/MS mode. Therefore, APCI/MS positive mode was used to analyze PAS,pterostilbene, and their metabolites, and ESI/MS negative mode was usedto analyze aspirin, pterostilbene, and their metabolites. PAS washydrolyzed in mice to generate metabolites of aspirin and pterostilbene;neither PAS nor its deacetylated metabolites were detected.

Using the same experimental conditions, RAS has also been shown to behydrolyzed in human colon cancer cells (HCT-116 and HT-29) to generateresveratrol and aspirin. Generally aspirin-stilbene derivativeconjugates can be hydrolyzed and are effective prodrugs of both aspirinand the stilbene derivatives.

Example 11 Xenograft Study

8 week old animals are randomized into 4 groups based on treatment(DMSO: n=7; RAS 50 mg/kg: n=7; RAS 100 mg/kg: n=7; R+As(resveratrol+aspirin in 1:1 molar ratio equivalent to 50 mg/kg RAS):n=7). Animals are implanted with 2×10⁶ HCT-116 cells on each flank.Starting one week post implantation, animals receive their respectivetreatments through oral gavage (100 μl in corn oil and 5% DMSO), 7×/weekfor up to 3 weeks. Tumor volume is measured every other day duringtreatment regimen. At no more than 3 weeks of treatment, animal aresacrificed. The tumors are weighed and evaluated for biomarker analysis,bioavailability and histological analysis.

Although the present invention has been described with reference tospecific details of certain embodiments thereof, it is not intended thatsuch details should be regarded as limitations upon the scope of theinvention except as and to the extent that they are included in theaccompanying claims. As noted above, the above-described embodiments canbe modified or varied without departing from the present invention. Itis therefore to be understood that, within the scope of the claims andtheir equivalents, the present invention can be practiced otherwise thanas specifically described above.

All patents, patent publications, non-patent publications referencedherein are incorporated by reference in their entireties for allpurposes and to the same extent as if each was specifically andindividually indicated to be incorporated by reference.

That which is claimed is:
 1. A compound having the following structure

or a pharmaceutically acceptable salt or prodrug thereof, wherein: R_(E)is —O—C(O)—C₁₋₃alkyl; R_(F) is

wherein n=3, 5, or 7; and R_(G) is —H or C₁₋₆ alkyl.
 2. The compound ofclaim 1, wherein R_(G) is —H or -Me; and R_(E) is —O—C(O)-Me,—O—C(O)-Et, or —O—C(O)—Pr.
 3. The compound of claim 1, wherein R_(E) is—O—C(O)-Me and R_(G) is -Me.
 4. The compound of claim 2, wherein R_(F)is

and n=3, 5, or
 7. 5. The compound of claim 2, wherein R_(F) is

and n=3, 5, or
 7. 6. The compound of claim 1, wherein said compound hasthe following structure:


7. The compound of claim 1, wherein said compound has the followingstructure:


8. A method of treating lung or colorectal cancer in a subject in needthereof, comprising: administering to said subject a therapeuticallyeffective amount of the following compound:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: R_(E)is —O—C(O)—C₁₋₃alkyl; R_(F) is

wherein n=3, 5, or 7; and R_(G) is —H or C₁₋₆ alkyl.
 9. The method ofclaim 8, wherein R_(G) is —H or -Me; and R_(E) is —O—C(O)-Me,—O—C(O)-Et, or —O—C(O)—Pr.
 10. The method of claim 9, wherein R_(E) is—O—C(O)-Me and R_(G) is -Me.
 11. The method of claim 9, wherein R_(F) is

and n=3, 5, or
 7. 12. The method of claim 9, wherein R_(F) is

and n=3, 5, or
 7. 13. The method of claim 8, wherein said compound hasthe following structure:


14. The method of claim 8, wherein said compound has the followingstructure:


15. A pharmaceutical composition, comprising: a compound having thefollowing structure:

or a pharmaceutically acceptable salt or prodrug thereof, and apharmaceutically acceptable carrier, wherein: R_(E) is—O—C(O)—C₁₋₃alkyl; R_(F) is

wherein n=3, 5, or 7; and R_(G) is —H or C₁₋₆ alkyl.
 16. Thepharmaceutical composition of claim 15, wherein R_(G) is —H or -Me; andR_(E) is —O—C(O)-Me, —O—C(O)-Et, or —O—C(O)—Pr.
 17. The pharmaceuticalcomposition of claim 16, wherein R_(E) is —O—C(O)-Me and R_(G) is -Me.18. The pharmaceutical composition of claim 16, wherein R_(F) is

and n=3, 5, or
 7. 19. The pharmaceutical composition of claim 16,wherein R_(F) is

and n=3, 5, or
 7. 20. The pharmaceutical composition of claim 15,wherein said compound has the following structure:


21. The pharmaceutical composition of claim 15, wherein said compoundhas the following structure: